Imino pyrrolidine derivatives useful as nitric oxide synthase inhibitors

ABSTRACT

The current invention discloses useful pharmaceutical compositions containing amidino derivative useful as nitric oxide synthase inhibitors.

This application is a divisional of U.S. patent application Ser. No.08/448,473 filed Jun. 6, 1995, now U.S. Pat. No. 5,854,234 incorporatedby reference, which claims priority to PCT application Ser. No.PCT/US94/11832, filed Oct. 20, 1994 which is a continuation-in-part ofU.S. patent application Ser. No. 08/141,168 filed Oct. 21, 1993 nowabandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to amidino derivatives, pharmaceuticalcompositions containing amidino derivatives, and to their use intherapy, in particular their use as nitric oxide synthase inhibitors.

2. Related Art

It has been known since the early 1980's that the vascular relaxationbrought about by acetycholine is dependent on the presence of theendothelium and this activity was ascribed to a labile humoral factortermed endothelium-derived relaxing factor (EDRF). The activity ofnitric oxide (NO) as a vasodilator has been known for well over 100years and NO is the active component of amylnitrite, glyceryltrinitriteand other nitrovasodilators. The recent identification of EDRF as NO hascoincided with the discovery of a biochemical pathway by which NO issynthesized from the amino acid L-arginine by the enzyme NO synthase.

NO is the endogenous stimulator of the soluble guanylate cyclase and isinvolved in a number of biological actions in addition toendothelium-dependent relaxation including cytotoxicity of phagocyticcells and cell-to-cell communication in the central nervous system (seeMoncada et al. Biochemical Pharmacology, 38, 1709-1715 (1989) andMoncada et al. Pharmacological Reviews, 43, 109-142 (1991). It is nowthought that excess NO production may be involved in a number ofconditions, particularly conditions which involve systemic hypotensionsuch as toxic shock and therapy with certain cytokines.

The synthesis of NO from L-arginine can be inhibited by the L-arginineanalogue, L-N-monomethyl-arginine (L-NMMA) and the therapeutic use ofL-NMMA for the treatment of toxic shock and other types of systemichypertension has been proposed (WO 91/04024 and GB-A-2240041). Thetherapeutic use of certain other NO synthase inhibitors apart fromL-NMMA for the same purpose has also been proposed in WO 91/04024 and inEP-A-0446699.

It has recently become apparent that there are at least three types ofNO synthase as follows:

(i) a constitutive, Ca⁺⁺/calmodulin dependent enzyme, located in theendothelium, that releases NO in response to receptor or physicalstimulation.

(ii) a constitutive, Ca⁺⁺/calmodulin dependent enzyme, located in thebrain, that releases NO in response to receptor or physical stimulation.

(iii) a Ca⁺⁺ independent enzyme which is induced after activation ofvascular smooth muscle, macrophages, endothelial cells, and a number ofother cells by endotoxin and cytokines. Once expressed this inducible NOsynthase synthesizes NO for long periods.

The NO released by the constitutive enzymes acts as a transductionmechanism underlying several physiological responses. The NO produced bythe inducible enzyme is a cytotoxic molecule for tumor cells andinvading microorganisms. It also appears that the adverse effects ofexcess NO production, in particular pathological vasodilation and tissuedamage, may result largely from the effects of NO synthesized by theinducible NO synthase.

There is also a growing body of evidence that NO may be involved in thedegeneration of cartilage which takes place in certain conditions suchas arthritis and it is also known that NO synthesis is increased inrheumatoid arthritis. Accordingly, further conditions in which there isan advantage in inhibiting NO production from L-arginine includeautoimmune and/or inflammatory conditions affecting the joints, forexample arthritis.

Conditions in which there is an advantage in inhibiting NO productionfrom L-arginine include systemic hypotension associated with septicand/or toxic shock induced by a wide variety of agents; therapy withcytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short termimmunosuppression in transplant therapy. Further conditions in whichthere is an advantage in inhibiting NO production from L-arginineinclude autoimmune diseases and/or inflammatory conditions such as thoseaffecting the joints, for example arthritis or inflammatory boweldisease, cardiovascular ischemia, diabetes, hyperalgesia (allodynia)cerebral ischemia (Both focal ischemia, thrombotic stroke and globalischemia, secondary to cardiac arrest) and other CNS disorders mediatedby NO.

Some of the NO synthase inhibitors proposed for therapeutic use so far,and in particular L-NMMA, are non-selective in that they inhibit boththe constitutive and the inducible NO synthase. Use of such anon-selective NO synthase inhibitor requires that great care be taken inorder to avoid the potentially serious consequences of over-inhibitionof the constitutive NO-synthase including hypertension and possiblethrombosis and tissue damage. In particular, in the case of thetherapeutic use of L-NMMA for the treatment of toxic shock it has beenrecommended that the patient must be subject to continuous bloodpressure monitoring throughout the treatment. Thus, while non-selectiveNO synthase inhibitors have therapeutic utility provided thatappropriate precautions are taken, NO synthase inhibitors which areselective in the sense that they inhibit the inducible NO synthase to aconsiderably greater extent than the constitutive NO synthase would beof even greater therapeutic benefit and easier to use.

WO 94/12165, WO 94/14780, WO93/13055, EP 0446699A1 and U.S. Pat. No.5,132,453 disclose compounds that inhibit nitric oxide synthesis andpreferentially inhibit the inducible isoform of nitric oxide synthase.The disclosures of which are hereby incorporated by reference in theirentirety as if written herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of orally administered 2-iminopiperidine (mg/kg)on LPS-induced increase in plasma nitrites in rat.

SUMMARY OF THE INVENTION

In a broad aspect, the present invention is directed to inhibiting ormodulating nitric oxide synthesis in a subject in need of suchinhibition or modulation by administering a compound whichpreferentially inhibits or modulates the inducible isoform of nitricoxide synthase over the constitutive isoforms of nitric oxide synthase.

The invention further relates to a pharmaceutical composition comprisinga compound having the formula (I):

and salts, pharmaceutically acceptable esters and prodrugs thereof,wherein:

X is selected from the group consisting of methylene, nitrogen, oxygen,S, SO, and SO₂ wherein nitrogen and lower alkyl radicals may optionallybe substituted with hydroxy, lower alkyl, lower alkoxy, amino, andhaloalkyl groups;

n=0 to about 7;

R¹ and R², are independently selected from the group consisting ofhydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, loweralkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano,sulfonyl, haloalkyl, carboalkoxy, carboaryloxy, carboalkylaryloxy,alicyclic hydrocarbon, heterocycly, aromatic hydrocarbon, —CONR⁵R⁶,—SO₂NR⁵R⁶, —COR⁵, —SO₂R⁵, alkyl sulfoxide, aryl sulfoxide, alkylsulfone, aryl sulfone, alkyl sulfate, aryl sulfate, and sulfonamide,wherein all said radicals can be optionally substituted with one or moreof the following:

hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy,lowerthioalkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl,carboalkoxy, carboaryloxy, carboxyalkylaryloxy, haloalkyl, —SO₂NR⁵R⁶ and—SO₂R⁵ wherein all said substitutions may be optionally substituted withone or more of the following: amino, carboxyl, carboalkoxy,carboaryloxy, carboxyalkylaryloxy and lower alkoxy;

and R¹, R², may optionally together form an alicyclic hydrocarbon,heterocycly or aromatic hydrocarbon and said optionally formed ring maybe optionally substituted with one or more of the following:

lower alkyl, lower alkenyl, lower alkynyl which may be optionallysubstituted with carboxyl,carboalkoxy, carboaryloxy, carboxyalkylaryloxyand lower alkoxy;

R³, R⁴ are independently selected from the group consisting of hydrogen,hydroxy, and alkyloxy;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, lower alkyl, and aryl; with the proviso that when n=1

and R¹ and/or R² are at position 3 or 4, neither R¹ or R² is aryl; and

together with at least one non-toxic pharmaceutical acceptable carrier.

n is preferably 1,2,3,4,5,6, or 7, more preferably n is 1-5, still moreprefered n is 1-4, most prefered n is 1-3.

Compounds and compositions defined above have usefulness as inhibitorsof nitric oxide synthase. These compounds also preferentially inhibitthe inducible form over the constitutive form.

DETAILED DESCRIPTION OF THE INVENTION

A preferred embodiment of the present invention is a pharmaceuticalcomposition of the formula;

X is selected from the group consisting of methylene, nitrogen, oxygenand sulfur;

n is an integer 0 to 5;

R¹ and R², are independently selected from the group consisting ofhydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, haloalkyl,aromatic hydrocarbon and alicyclic hydrocarbon wherein all said radicalsare optionally substituted with one or more of the following: carboxyl,carboalkoxy, amino, lower alkoxy, lower thioalkoxy and lower alkylwherein all said substitutions may be optionally substituted with one ormore of the following:amino, carboxyl, and carboalkoxy;

and R¹, R², may optionally together form an alicyclic hydrocarbon oraromatic hydrocarbon; and

R³, R⁴ are independently selected from the group consisting of hydrogenand hydroxy.

Another preferred embodiment of the present invention is a compound ofthe formula:

and salts, pharmaceutically acceptable ester and prodrugs thereof,wherein:

X is selected from the group consisting of methylene, nitrogen, oxygen,sulfur, SO, or SO₂;

n=o to about 7;

R¹ and R², are independently selected from the group consisting ofhydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, loweralkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano,sulfonyl, haloalkyl, carboalkoxy, carboaryloxy, carboalkylargyloxy,alicyclic hydrocarbon, heterocycly, aromatic hydrocarbon, —CONR⁵R⁶,—SO₂nR⁵R⁶, —COR⁵, —SO₂R⁵, alkyl sulfoxide, aryl sulfoxide, alkylsulfone, aryl sulfone, alkyl sulfate, aryl sulfate, and sulfonamide,wherein all said radicals are optionally substituted with one or more ofthe following: hydroxy, alkyl, lower alkenyl, lower alkynyl, loweralkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl, carboalkoxy,carboaryloxy, carboxy alkylaryloxy, haloalkyl, —SO₂NR⁵R⁶ and —SO₂R⁵wherein all said substitutions may be optionally substituted with one ormore of the following: amino, carboxyl,carboalkoxy, carboaryloxy,carboxyalkylaryloxy and lower alkoxy;

and R¹, R²may optionally together form an alicyclic hydrocarbon,heterocycly or aromatic hydrocarbon and said optionally formed ring maybe optionally substituted with one or more of the following lower alkyl,lower alkenyl, lower alkynyl which may be optionally substituted withcarboxyl,carboalkoxy, carboaryloxy, carboxyalkylaryloxy and loweralkoxy;

R³, R⁴ are hydrogen,hydroxy, and alkyloxy;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, lower alkyl, and aryl;

with the proviso that when n=1

and R¹ and/or R² are at position 3 or 4, neither R¹ or R² is aryl andwith the futher proviso that when X is methylene, nitrogen, oxygen, orsulfur then R¹ and R² cannot be both H, or be a haloalkyl and where N=3R¹ cannot be Methyl at postion 7.

The present invention includes compounds listed above in the form ofsalts, in particular acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable although salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Thus,preferred salts include those formed from hydrochloric, hydrobromic,sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic,ethanesulphonic, ρ-toluenesulphonic, benzenesulphonic and isethionicacids. Salts of the compounds of formula (I) can be made by reacting theappropriate compound in the form of the free base with the appropriateacid.

While it may be possible for the compounds of formula (I) to beadministered as the raw chemical, it is preferable to present them as apharmaceutical formulation. According to a further aspect, the presentinvention provides a pharmaceutical formulation comprising a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof,together with one or more pharmaceutically acceptable carriers thereofand optionally one or more other therapeutic ingredients. The carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), rectal and topical (including dermal, buccal,sublingual and intraocular) administration although the most suitableroute may depend upon for example the condition and disorder of therecipient. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. All methods include the step of bringing into association acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof (“active ingredient”) with the carrier which constitutes one ormore accessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain antioxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example, saline, water-for-injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

Preferred unit dosage formulations are those containing an effectivedose, as hereinbelow recited, or an appropriate fraction thereof, of theactive ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The compounds of the invention may be administered orally or viainjection at a dose of from 0.1 to 500 mg/kg per day. The dose range foradult humans is generally from 5 mg to 2 g/day. Tablets or other formsof presentation provided in discrete units may conveniently contain anamount of compound of the invention which is effective at such dosage oras a multiple of the same, for instance, units containing 5 mg to 500mg, usually around 10 mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diets, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the particular diseaseundergoing therapy.

The compounds of formula (I) are preferably administered orally or byinjection (intravenous or subcutaneous). The precise amount of compoundadministered to a patient will be the responsibility of the attendantphysician. However, the dose employed will depend on a number offactors, including the age and sex of the patient, the precise disorderbeing treated, and its severity. Also, the route of administration mayvary depending on the condition and its severity.

As utilized herein, the term “lower alkyl”, alone or in combination,means an acyclic alkyl radical containing from 1 to about 10, preferablyfrom 1 to about 8 carbon atoms and more preferably 1 to about 6 carbonatoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl and the like.

The term “lower alkenyl” refers to an unsaturated acyclic hydrocarbonradical in so much as it contains at least one double bond. Suchradicals containing from about 2 to about 10 carbon atoms, preferablyfrom about 2 to about 8 carbon atoms and more preferably 2 to about 6carbon atoms. Examples of suitable alkenyl radicals include propylenyl,buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-1-yl,3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl, and thelike.

The term “lower alkynyl” refers to an unsaturated acyclic hydrocarbonradicals in so much as it contains one or more triple bonds, suchradicals containing about 2 to about 10 carbon atoms, preferably havingfrom about 2 to about 8 carbon atoms and more preferably having 2 toabout 6 carbon atoms. Examples of suitable alkynyl radicals includeethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl,3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl,3,3-dimethylbutyn-1-yl radicals and the like.

The term “alicyclic hydrocarbon” means a aliphatic radical in a ringwith 3 to about 10 carbon atoms, and preferably from 3 to about 6 carbonatoms. Examples of suitable alicyclic radicals include cyclopropyl,cyclopropylenyl, cyclobutyl, cyclopentyl, cyclohexyl,2-cyclohexen-1-ylenyl, cyclohexenyl and the like.

The term “aromatic hydrocarbon radical” means 4 to about 16 carbonatoms, preferably 6 to about 12 carbon atoms, more preferably 6 to about10 carbon atoms. Examples of suitable aromatic hydrocarbon radicalsinclude phenyl, naphthyl, and the like.

The term “acyloxy” means 1 to about 4 carbon atoms. Suitable examplesinclude alkanoyloxy, benzoyloxy and the like.

The term “heterocyclic radical” means a saturated or unsaturated cyclichydrocarbon radical with 4 to about 10 carbon atoms, preferably about 5to about 6; wherein 1 to about 3 carbon atoms are replaced by nitrogen,oxygen or sulfur. The “heterocyclic radical” may be fused to an aromatichydrocarbon radical. Suitable examples include pyrrolyl, pyridinyl,pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl,imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl,3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2-imidazonlinyl,imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl,4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl,1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, quinolinyl, andthe like.

The term “lower alkoxy”, alone or in combination, means an alkyl etherradical wherein the term alkyl is as defined above and most preferablycontaining 1 to about 4 carbon atoms. Examples of suitable alkyl etherradicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “lower thioalkoxy” means the same as “alkoxy” except sulfurreplaces oxygen.

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “haloalkyl” means a lower alkyl as defined above having 1-5preferably 1-3 halogens attached to said lower alkyl chain.

The term “prodrug” refers to a compound that is made more active invivo.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis.

All references, patents or applications, U.S. or foreign, cited in theapplication are hereby incorporated by reference as if written herein.

The following schemes can be used to practice the present invention.

The invention is illustrated by the following examples. Some of thecompounds disclosed are publicly available from the source cited.

EXAMPLE 1 2-Imino-heptamethyleneimine hydrochloride

To a 50 mL flask was added 5 g (0.04 mol) of 2-oxo-heptamethyleneimineand 15 mL of benzene. This was stirred at reflux while 4.8 g (0.038 mol)of dimethylsulfate were added dropwise. After the addition was complete,stirring was continued at reflux for 18 hours. The heat was thenremoved, the reaction mixture was diluted with ethyl acetate (EtOAc) andwashed with two 100 mL portions of aqueous potassium carbonate (K₂CO₃).The organic layer was dried (MgSO₄), filtered and concentrated to afford4.2 g of the iminoether as a yellow oil. 2.2 g (0.016 mol) of theiminoether were dissolved in 50 mL of anhydrous ethanol (EtOH) and 0.85g (0.016 mol) of ammonium chloride was added. This mixture was stirredat 25° C. for three days. Removal of the solvent in vacuo afforded 1.7 g(48%) of the 2-imino-heptamethyleneimine hydrochloride as a white solid,mp 166-175° C. MH⁺=127.

Elemental analysis: C₇H₁₄N₂.HCl.1/4H₂O

C H N Calculated: 50.30 9.35 16.76 Found: 49.95 9.22 17.12

EXAMPLE 2 2-Imino-octamethyleneimine hydrochloride

To a 100 mL flask was added 5 g (0.035 mol) of 2-oxo-octamethyleneimineand 15 mL of benzene. This was stirred at reflux while 4.4 g (0.035 mol)of dimethylsulfate was added dropwise. After the addition were complete,stirring was continued at reflux for 18 hours. The heat was thenremoved, the reaction mixture was diluted with EtOAc and washed with two100 mL portions of aqueous potassium carbonate. The organic layer wasdried (MgSO₄), filtered and concentrated to afford 4.4 g of theiminoether as a yellow oil. The iminoether was dissolved in 50 mL ofanhydrous EtOH and 1.5 g (0.028 mol) of ammonium chloride was added.This mixture was stirred at 25° C. for six days. Removal of the solventin vacuo afforded 2.75 g (45%) of the 2-imino-octamethyleneiminehydrochloride as a white solid, mp 108-128° C. MH⁺=141.

Elemental analysis: C₈H₁₆N₂.HCl.1/3 H₂O

C H N Calculated: 52.77 9.74 15.35 Found: 53.05 9.41 14.98

EXAMPLE 3 3,4,5,6,7,8-hexahydro-2[1H]-quinolineimine hydroiodide

3,4,5,6,7,8-Hexahydro-2[1H]-quinolinone (3.0 g, 20 mmol),2,4-bis(4-methoxy-phenyl)1,3-dithia-2,4-diphosphetane 2,4-disulfide (4.0g, 10 mmol), and 100 ml of toluene were mixed and refluxed for threehours. The dark brown solution was cooled to room temperature, andfiltered. The filtrate was rotary evaporated. The residue was dissolvedin methylene chloride (CH₂Cl₂) and applied to a column of silica gelequilibrated with Ch₂Cl₂. The thioamide rich fractions, identified bymass spectroscopic analyses, were combined and evaporated. The residue(0.38 g, 2.3 mmol) was treated with methyl iodide (0.36 g, 2.6 mmol) inacetone at 20° C. for four hours. After rotary evaporation, the residuewas washed with (Et₂O), several times. The residue was treated withammonia-saturated EtOH at 20° C. for 12 hours. After evaporation, theresidue was washed with Et₂O, and recrystallized from a mixture of EtOHand Et₂O. The product was isolated as pale yellow solid and the massspectrum was consistent with the proposed structure. (MH⁺=150.1); m.p.150-155° C.

EXAMPLE 4 2-Imino-3-methyltetramethyleneimine hydriodide

The title compound was prepared by the method of EXAMPLE 3.3-Methyl-2-pyrrolidinone (5.0 g, 50 mmol) was converted to the thioamidewhich was reacted with methyl iodide,, and treated subsequently withammonia-saturated ethyl alcohol. The product was isolated as a whiteamorphous solid with mass spectrum consistent with the proposedstructure. (MH+=98.4); m.p. 73-75° C.

EXAMPLE 5 2-Imino-5-methyltetramethyleneimine hydriodide

The method of preparation of 3,4,5,6,7,8-nexahydro-2[1H]quinolineiminehydriodide, EXAMPLE 3, was used to convert 5-methyl-2-pyrrolidone to thetitle compound which was obtained as white solid. The mass spectrum ofthe product was found to be consistent with the proposed structure.(MH+=98.4); m.p. 83-85° C.

EXAMPLE 6 2-Imino-4-methylpiperidine acetate

2-Amino-4-methylpyridine (1.56 g; 15 mmoles) and 5% rhodium on carbon(0.51 g, wet, Degussa type G10) in glacial acetic acid (30 mL) wereshaken on a Parr hydrogenation apparatus at 55 psi of hydrogenovernight. The catalyst was removed by filtration and the filtrate wasdiluted with water to 250 mL, and lyophilized to yield a light tanpowder. The powder was recrystallized from warm ethanol/ether to give0.3 g of white solid. mp 181-182° C. A second crop of white solid wasobtained (0.85 g; mp 180-182° C.). MH+=113; ¹H NMR (D₂O): δ3.32-3.16 (m,2H); 2.54-2.46 (m, 1H); 2.10-2.00 (m, 1H); 1.80-1.70 (m, 2H); 1.74 (s,3H); 1.32-1.25 (m, 1H); 0.87 (d, J=6.6 Hz, 3H).

Elemental analysis: C₆H₁₂N₂.CH₃COOH

C H Calculated: 55.79 9.36 Found: 55.85 9.22

EXAMPLE 7 2-Imino-5-methylpiperidine acetate

The method of preparation of 2-imino-4-methylpiperidine acetate, EXAMPLE6, was used to convert 2-amino-5-methylpyridine to the title compoundwhich was obtained as a white solid. The analysis of the product wasfound to be consistent with the proposed structure. m.p. 175-178° C.MH+=113; d¹H NMR (D₂O): δ3.28-3.21 (m, 1H); 2.79-2.70 (m, 1H); 2.49-2.43(m, 2H); 1.79-1.67 (m, 2H); 1.73 (s, 3H); 1.30-1.23 (m, 1H); 0.82 (d,J=6.6 Hz, 3H).

Elemental analysis: C₆H₁₂N₂.CH₃COOH

C H Calculated: 55.79 9.36 Found: 55.81 9.39

EXAMPLE 8 2-Imino-6-methylpiperidine hydrochloride

The method of preparation of 2-imino-4-methylpiperidine acetate, EXAMPLE6, was used to convert 2-amino-6-methylpyridine to the title compoundwhich was obtained as a white solid. The analysis of the product wasfound to be consistent with the proposed structure. m.p. 160-162° C.MH+=113; ¹H NMR (D₂O): δ3.58-3.40 (m, 1H); 2.60-2.35 (m, 2H) ; 1.95-1.70(m, 2H); 1.68-1.50 (m, 1H) 1.40-1.35 (m, 1H); 1.05 (d, J=6.6 Hz, 3H).

Elemental analysis: C₆H₁₂N₂.HCl

C H N Calculated: 48.49 8.82 18.85 Found: 48.32 9.01 18.70

EXAMPLE 9 2-imino-3-methylpiperidine acetate

The method of preparation of 2-imino-3-methylpiperidine acetate, EXAMPLE6, was used to convert 2-amino-6-methylpyridine to the title compoundwhich was obtained as a white solid. The analysis of the product wasfound to be consistent with the proposed structure. m.p. 88-100° C.MH+=113 ; ¹H NMR (D₂O): δ3.22-3.15 (m, 2H); 2.67-2.55 (m, 1H); 1.80-1.40(m, 4H); 1.75 (s, 3H); 1.17 (d, J=7.2 Hz, 3H).

Elemental analysis: C₆H₁₂N₂.CH₃COOH.3/4H₂O

C H N Calculated: 51.73 9.50 15.08 Found: 51.87 9.29 15.04

EXAMPLE 10 2-imino-4,6-dimethylpiperidine acetate

The method of preparation of 2-Imino-3-methylpiperidine acetate, EXAMPLE6, was used to convert 2-amino-4,6-dimethylpyridine to the titlecompound which was obtained as a white solid. The analysis of theproduct was found to be consistent with the proposed structure. m.p.163-166° C. MH+=127 ; ¹H NMR (D₂O): δ3.48-3.40 (m, 1H); 2.52-2.40 (m,1H); 2.07-1.95 (m, 1H); 1.85-1.75 (m, 2H); 1.75 (s, 3H); 1.12 (d, J=6.3Hz, 3H); 1.02-0.92 (m, 1H); 0.86 (d, J=6.3 Hz, 3H).

Elemental analysis: C₇H₁₄N₂.CH₃COOH

C H N Calculated: 58.04 9.74 15.04 Found: 57.86 10.09 15.01

EXAMPLE 11 2-Imino-3-hydroxypiperidine acetate

The method of preparation of 2-imino-3-methylpiperidine acetate, EXAMPLE6, was used to convert 2-amino-3-hydroxypyridine to the title compoundwhich was obtained as a white solid. The analysis of the product wasfound to be consistent with the proposed structure. m.p. 128-130° C.MH+=115 ; ¹H NMR (D₂O): δ4.34-4.28 (m, 1H); 3.20-3.10 (m, 2H); 2.05-1.50(m, 4H); 1.71 (s, 3H).

Elemental analysis: C₇H₁₀N₂₀.CH₃COOH

C H N Calculated: 48.27 8.10 16.08 Found: 48.04 8.48 15.96

Additional compounds of this invention include:

EXAMPLE 12 2-iminopyrrolidine hydrochloride; E. J. Moriconi and A. A.Cevasco, J. Org. Chem. 33, 2109-2111 (1968)

EXAMPLE 13 2-Iminopiperidine hydrochloride; Aldrich Chemical Co.

EXAMPLE 14 2-Iminotetrahydropyrimidine hemihydrosulfate; D. J. Brown andR. F. Evans, J. Chem. Soc. 4039-4045 (1962)

EXAMPLE 15 2-Iminoimidazolidine D. Stefanye and W. C. Howard, J. Amer.Chem. Soc., 77, 761-762 (1955)

EXAMPLE 16 2-Iminothiazolidine hydrochloride; Aldrich Chemical Co.

EXAMPLE 17 2-Imino-3-thiapiperidine hydrochloride; D. L. Klayman and T.S. Woods, J. Org. Chem., 39, 1819-1823 (1974)

EXAMPLE 18 2-Imino-3-oxopiperidine hydrochloride; B. Adcock and A.Lawson, J. Chem.Soc. 474-479 (1965)

EXAMPLE 19 2-Iminooxazolidine; Transworld Chemical Inc.

EXAMPLE 20 5-Chloromethyl-2-iminooxazolidine; Janssen Chimica

EXAMPLE 21 2-Iminobiotin; Sigma Chemical Co.

EXAMPLE 22 2-Iminobiotin ethyl ester

EXAMPLE 23 1-Methyl-2-iminotetrahydropyrimidine; GER 765,547

EXAMPLE 24 4-ethylcyclohexanone, oxime

A sample of 4-ethylcyclohexanone (Aldrich, 4.9 g, 38.8 mmol) wascombined with NH₂OH.HCl (4.0 g, 58.3 mmol) and sodium acetate (NaOAc,5.7 g, 69.8 mmol) in a mixture of ethanol (EtOH, 35 mL) and water (25mL). This mixture was refluxed for 5 h under a nitrogen atmosphere.After the reaction was cooled to room temperature and stirred for anadditional 5 days, all solvent was removed under reduced pressure. Theresidue was partitioned between ethyl acetate (EtOAc) and water and theorganic phase was washed with 1×75 mL of saturated NaCl (brine), driedover Na₂SO₄, and stripped of all solvent under reduced pressure. Thisprovided 5.5 g (100%) of the title compound as light yellow mobile oil.This material showed a retention time of 9.83 min (100% purity by peakarea integration) on a Shimadzu GC-14A gas chromatograph (GC) with a0.25 mm×25 M methyl, 5% phenylsilicone column and NMR and IR spectraconsistent with the assigned structure.

Elemental analysis: C₈H₁₅NO.H₂O (MW=159.23)

C H N Calculated: 60.35 10.76 8.80 Found: 60.64 9.25 8.41

EXAMPLE 25 5-ethyl-hexahydro-1H-azepin-2-one

A 5.3 g (37.7 mmol) sample of the title material of EXAMPLE 24 was addedto a dropping funnel containing 6 mL of 80% H₂SO₄. After using astirring rod to obtain a turbid solution, this mixture was addeddropwise (10 min) to 5 mL of 80% H₂SO₄ stirred magnetically andmaintained at 120° C. with an external oil bath. Within 5 minutes of thestart of addition an exotherm was noted and the temperature of thereaction rose to 160° C. before cooling again to 120° C. Ten minuteslater the flask was removed from the bath and allowed to cool to roomtemperature. The product mixture was diluted with water (20 mL) andbrought to pH 6 with concentrated NH₄₀H. This solution was furtherdiluted with 75 mL of water and extracted with 3×75 mL of CH₂Cl₂. Thecombined organic phase was washed with 1×50 mL of brine, dried (Na₂SO₄),filtered, and stripped of all solvent under reduced pressure. The oilyresidue was purified by HPLC on silica gel to yield 3.73 g (70%) of thetitle product as a cream colored solid. This material had a GC retentiontime of 13.17 min and peak area integration of 100% under conditionsidentical to those used for the product of EXAMPLE 24.

Elemental analysis: C₈H₁₅NO.0.05 H₂O (MW=142.12)

C H N Calculated: 67.61 10.71 9.86 Found: 67.47 10.67 9.90

EXAMPLE 26 4-ethyl-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

To a magnetically stirred slurry of trimethyloxonium tetrafluoroborate(Lancaster, 0.62 g, 4.2 mmol) in CH₂Cl₂ (15 mL) under argon (Ar) wasadded the title product of EXAMPLE 25 (0.50 g, 3.5 mmol). This mixturewas stirred at room temperature for 12 h before it was diluted with 10mL of CH₂Cl₂ and partitioned between 40 mL of saturated KHCO₃ and 50 mLof EtOAc. The organic phase was separated, dried over Na₂SO₄, filtered,and stripped of all solvent under reduced pressure to provide the crudetitle product as a pale yellow oil. This material was chromatographed ona short path Merck flash silica column eluting with EtOAc/n-hexane(1:1). The title pale yellow liquid product had a GC retention time of8.56 min (100%) and NMR and IR sprectra consistent with the indicatedproduct.

EXAMPLE 27 5-ethyl-hexahydro-1H-azepin-2-imine, monohydrochloride

The title product of EXAMPLE 26 (0.28 g, 1.80 mmol) and 0.11 g (2.0mmol) of ammonium chloride (NH₄Cl) were refluxed in 20 mL of methanol(MeOH) under a nitrogen atmosphere for 3.5 h. After cooling the reactionto room temperature, it was filtered, stripped of all solvent underreduced pressure, and partitioned between 20 mL of water and 25 mL ofEtOAc. The organic and aqueous phases were separated and the aqueousphase was washed with another 25 mL portion of EtOAc before it waslyophilized to provide 0.27 g (80%) of the white solid title material.

HRMS (EI) calcd for C₈H₁₆N₂ m/e 140.131, found m/e 140.131. ¹HNMR(CD3OD): δ3.50-3.36 (m, 2H), 2.79-2.60 (m, 2H), 1.99-2.08 (m, 1H),1.96-1.87 (m, 1H), 1.56 (m, 1H), 1.36 (m, 2H) 1.27-1.12 (m, 2H), 0.94(t, 3H, J=7.5 Hz).

Elemental analysis: C₈H₁₆N₂.HCl.0.1 H₂O.0.2 NH₄Cl (MW=189.19)

C H N Cl Calculated: 50.79 9.59 16.26 22.49 Found: 50.71 9.48 16.3022.45

EXAMPLE 28 4-phenylcyclohexanone, oxime

A sample of 4-phenylcyclohexanone (Aldrich, 10.0 g, 57.4 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 6.0 g(86.1 mmol) of hydroxylamine hydrochloride and 8.5 g (103.3 mmol) ofNaOAc in a mixture of 75 mL of EtOH and 50 mL of water. The procedureproduced 10.2 g (94%) of the title material as a white solid.

Elemental analysis: C₁₂H₁₅NO (MW=189.26)

C H N Calculated: 76.16 7.99 7.40 Found: 75.96 7.89 7.33

EXAMPLE 29 hexahydro-5-phenyl-1H-azepin-2-one

To the title product of EXAMPLE 28 (9.0 g, 47.6 mmol) in 50 mL ofacetone was added 1N NaOH (52.4 mL, 52.4 mmol). After cooling thismixture in an ice bath, benzene sulfonylchloride (8.5 g, 48.0 mmol) wasadded drop-wise over 5 minutes to the stirred reaction mixturemaintained under a N₂ atmosphere. The reaction was allowed to warm toroom temperature and stir for 1 week. A white solid was filtered fromthe reaction mixture and washed with acetone to yield 4.2 g of the titlematerial. The filtrate was concentrated and partitioned between EtOAcand brine. The organic layer was dried (Na₂SO₄), filtered, and strippedof all solvent under reduced pressure. The residue solid was trituratedwith EtOAc/n-hexane (1:1) and filtered to provide an additional 2.9 g(total yield=80%) of the title lactam.

Elemental analysis: C₁₂H₁₅NO (MW=189.26)

C H N Calculated: 76.16 7.99 7.40 Found: 75.95 8.16 7.28

EXAMPLE 30 3,4,5,6,-tetrahydro-7-methoxy-4-phenyl-2H-azepine

The product of EXAMPLE 29 (2.0 g, 10.5 mmol) was reacted withtrimethyloxonium tetrafluoroborate (2.0 g, 13.6 mmol) by the method ofEXAMPLE 26 to yield 1.9 g (89%) of the title material.

Elemental analysis: C₁₃H₁₇NO.0.5 H₂O (MW=209.23)

C H N Calculated: 74.63 8.51 6.69 Found: 74.77 8.14 6.65

EXAMPLE 31 hexahydro-5-phenyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 30 (1.7 g, 8.6 mmol) in 20 mL of MeOH was reactedwith ammonium chloride (0.43 g, 8.0 mmol) by the method of EXAMPLE 27 toyield 1.7 g (91%) of the title material.

HRMS (EI) calcd for C₁₂H₁₆N₂ m/e 188.131, found m/e 188.133. ¹HNMR(CD₃OD): δ7.33-7.26 (m, 2H), 7.25-7.17 (m, 3H), 3.60-3.53 (m, 2H),2.98-2.87 (m, 2H), 2.78-2.69 (m, 1H), 2.17-2.08 (m, 1H), 2.05-1.98 (m,1H), 1.80-1.69 (m, 2H).

Elemental analysis: C₁₂H₁₆N₂.HCl.0.33 H₂O (MW=230.68)

C H N Cl Calculated: 62.48 7.72 12.14 15.37 Found: 62.41 7.54 12.1315.63

EXAMPLE 32 3, 5-dimethylcyclohexanone, oxime

A sample of 3,5-dimethylcyclohexanone (TCI, 22.6 g, 180 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 18.7 g(270 mmol) of hydroxylamine hydrochloride and 26.6 g (324 mmol) of NaOAcin a mixture of 200 mL of EtOH and 110 mL of water. The procedureproduced 23.1 g (94%) of the title material as a white solid.

Elemental analysis: C₈H₁₅NO.0.1 H₂O (MW=143.02)

C H N Calculated: 67.19 10.71 9.79 Found: 67.37 10.52 9.78

EXAMPLE 33 hexahydro-4,6-dimethyl-1H-azepine-2-one

A sample of the product of EXAMPLE 32 (10.0 g, 69.9 mmol) was convertedto the title compound as a mixture of two diastereomeric pairs by themethod of EXAMPLE 25 using 22 mL of 80% H₂SO₄. The procedure produced8.4 g (85%) of the title material as a pale yellow tacky solid.

Elemental analysis: C₈H₁₅NO (MW=141.21)

C H N Calculated: 68.04 10.71 9.92 Found: 67.92 10.04 9.83

EXAMPLE 34 3,4,5,6-tetrahydro-7-methoxy-3,5-dimethyl-2H-azepine

The product of EXAMPLE 33 (2.0 g, 14.2 mmol) was reacted withtrimethyloxonium tetrafluoroborate (2.7 g, 18.4 mmol) by the method ofEXAMPLE 26 to yield 1.9 g (73%) of the title material.

Elemental analysis: C₉H₁₇NO.0.125 H₂O (MW=157.49)

C H N Calculated: 68.64 11.04 8.89 Found: 68.66 11.14 8.87

EXAMPLE 35 hexahydro-4,6-dimethyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 34 (1.75 g, 8.6 mmol) in 25 mL of MeOH wasreacted with ammonium chloride (0.48 g, 9.0 mmol) by the method ofEXAMPLE 27 to yield 1.4 g (83%) of the title material.

HRMS (EI) calcd for C₈H₁₆N2 m/e 140.131, found m/e 140.130. ¹HNMR(CD3OD): δ3.26-3.18 (m, 1H), 2.42 (m, 1H), 1.91 (m, 1H), 1.85-1.62(m, 2H), 1.09 (d, 3H, J=6.8 Hz), 0.95 (d, 3H, J=6.8 Hz).

Elemental analysis: C₈H₁₆N₂.HCl.0.25 H₂O (MW=181.195)

C H N Cl Calculated: 53.03 9.74 15.46 19.57 Found: 53.19 9.85 15.4619.26

EXAMPLE 36 2,6-dimethylcyclohexanone, oxime

A sample of 2,6-dimethylcyclohexanone (Aldrich, 20.0 g, 158.5 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 16.5 g(237.6 mmol) of hydroxylamine hydrochloride and 23.4 g (285.1 mmol) ofNaOAc in a mixture of 150 mL of EtOH and 100 mL of water. The procedureproduced 20.3 g (88%) of the title material as a white crystallinesolid.

Elemental analysis: C₈H₁₅NO.0.25 H₂O (MW=145.72)

C H N Calculated: 65.94 10.72 9.61 Found: 65.74 10.45 9.67

EXAMPLE 37 hexahydro-3,7-dimethyl-1H-azepin-2-one Diastereomeric pair-Aand Diastereomeric pair-B

A sample of the product of EXAMPLE 36 (8.14 g, 57.6 mmol) was convertedto the title mixture of two diastereomeric pairs by the method ofEXAMPLE 25 using 15 mL of 80% H₂SO₄. Normal phase silica gelchromatography was used to separate the two diastereomeric pairs byelution with 3-10% isopropanol/n-heptane. The procedure generated 3.3 g(41%) of the title enantiomeric pair-A eluting first from the column and1.05 g (13%) material of the title enantiomeric pair-B eluting secondfrom the column both as white solids.

Enantiomeric Pair-A:

Elemental analysis: C₈H₁₅NO.0.05 H₂O (MW=142.12)

C H N Calculated: 67.61 10.71 9.86 Found: 67.83 10.71 9.87

Enantiomeric Pair-B:

Elemental analysis: C₈H₁₅NO (MW=141.214)

C H N Calculated: 68.04 10.71 9.92 Found: 68.94 10.88 9.43

EXAMPLE 38 3,4,5,6-tetrahydro-7-methoxy-2,6-dimethyl-2H-azepineEnantiomeric pair-A

Enantiomeric pair-A of EXAMPLE 37 (2.0 g, 14.1 mmol) was reacted withtrimethyloxonium tetrafluoroborate (2.7 g, 18.4 mmol) by the method ofEXAMPLE 26 to yield 1.9 g (86%) of the title material as a clearvolatile liquid.

EXAMPLE 39 hexahydro-3,7-dimethyl-1H-azepin-2-imine, monohydrochlorideEnantiomeric pair-A

The product of EXAMPLE 38 (1.24 g, 8.0 mmol) in 25 mL of MeOH wasreacted with ammonium chloride (0.37 g, 6.8 mmol) by the method ofEXAMPLE 27 to yield 1.23 g (91%) of the title material.

MS (EI) calcd for C₈H₁₆N₂ m/e 140.131, found m/e 140 (100%). ¹HNMR(CD₃OD): δ3.89-3.79 (m, 1H), 3.10-3.00 (m, 1H), 1.98-1.90 (m, 1H),1.87-1.75 (m, 3H), 1.54-1.32 (m, 2H), 1.32 (d, 3H, J=6.7 Hz), 1.26 (d,3H, J=7.0 Hz).

Elemental analysis: C₈H₁₆N₂.HCl.0.125 H₂O.0.05 NH₄Cl (MW=181.62)

C H N Cl Calculated: 52.91 9.68 15.81 20.50 Found: 52.89 9.63 15.4920.76

EXAMPLE 40 3,4,5,6-tetrahydro-7-methoxy-2,6-dimethyl-2H-azepineEnantiomeric pair-B

Enantiomeric pair-B of EXAMPLE 37 (510 mg, 3.6 mmol) was reacted withtrimethyloxonium tetrafluoroborate (694 mg, 4.7 mmol) by the method ofEXAMPLE 26 to yield 480 mg (86%) of the title material as a clearvolatile liquid.

EXAMPLE 41 hexahydro-3,7-dimethyl-1H-azepin-2-imine, monohydrochlorideEnantiomeric pair-B

The product of EXAMPLE 40 (380 mg, 2.4 mmol) in 15 mL of MeOH and 5 mLof CH₂Cl₂ was reacted with ammonium chloride (104 mg, 2.0 mmol) by themethod of EXAMPLE 27 to yield 368 mg (100%) of the title material.

MS (EI) calcd for C₈H₁₆N₂ m/e 140.131, found m/e 140.132 (100%). ¹HNMR(CD₃OD): δ3.85 (m, 1H), 3.00 (m, 1H), 1.95-1.70 (m, 5H), 1.42 (m,1H), 1.40 (d, 3H, J=7 Hz), 1.30 (d, 3H, J=6 Hz)

Elemental analysis: C₈H₁₆N₂.HCl.0.1 H₂O.0.1 NH₄Cl (MW=183.84)

C H N Cl Calculated: 52.27 9.65 16.00 21.21 Found: 52.44 10.16 15.8521.23

EXAMPLE 42 2-methylcyclohexanone, oxime

A sample of 2-methylcyclohexanone (Aldrich, 11.2 g, 100.0 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 13.9 g(200.0 mmol) of hydroxylamine hydrochloride and 17.2 g (210.0 mmol) ofNaOAc in a mixture of 160 mL of EtOH and 160 mL of water. The procedureproduced 10.1 g (79%) of the title material as a white solid.

EXAMPLE 43 hexahydro-3-methyl-1H-azepin-2-one, mixture withhexahydro-7-methyl-1H-azepin-2-one

A sample of the product of EXAMPLE 42 (5.1 g, 40.0 mmol) was convertedto the title compound mixture of two regioisomers by the method ofEXAMPLE 25 using 10 mL of 80% H₂SO₄. The procedure produced 3.1 g (62%)of the title materials. This mixture was subjected to silica gelchromatography eluting with 3-7% isopropanol/n-heptane to obtainIsomer-A (525 mg) and Isomer-B (735 mg).

EXAMPLE 44 3,4,5,6-tetrahydro-7-methoxy-6-methyl-2H-azepine

The Isomer-A product of EXAMPLE 43 (511 mg, 4.1 mmol) was reacted withtrimethyloxonium tetrafluoroborate (227 mg, 5.5 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 505 mg (87%) of the titlematerial.

EXAMPLE 45 3,4,5,6-tetrahydro-7-methoxy-2-methyl-2H-azepine

The Isomer-B product of EXAMPLE 43 (762 mg, 6.0 mmol) was reacted withtrimethyloxonium tetrafluoroborate (1.15 g, 7.8 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 780 mg (92%) of the titlematerial.

EXAMPLE 46 hexahydro-3-methyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 44 (294 mg, 2.1 mmol) in 14.5 mL of MeOH wasreacted with ammonium chloride (103 mg, 2.0 mmol) by the method ofEXAMPLE 27 to yield 260 mg (77%) of the title material.

MS (EI) calcd for C₇H₁₄N₂ m/e 126.116, found m/e 126 (100%). ¹HNMR(CD₃OD): δ3.51-3.42 (m, 2H), 3.06-3.00 (m, 1H), 1.99-1.93 (m, 1H),1.82-1.73 (m, 3H), 1.61-1.50 (m, 2H), 1.30 (d, 3H, J=7.14 Hz).

Elemental analysis: C₇H₁₄N₂.HCl.0.2 H₂O.0.1 NH₄Cl (MW=171.62)

C H N Cl Calculated: 48.99 9.28 17.14 22.72 Found: 48.95 9.60 17.2922.59

EXAMPLE 47 hexahydro-7-methyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 45 (125 mg, 0.89 mmol) in 9.0 mL of MeOH wasreacted with ammonium chloride (44.0 mg, 0.83 mmol) by the method ofEXAMPLE 27 to yield 101 mg (63%) of the title material.

MS (EI) calcd for C₇H₁₄N₂ m/e 126.116, found m/e 126 (100%). ¹HNMR(CD3OD): δ3.77 (m, 1H), 2.77 (ddd, 1H), 2.62 (m, 1H), 2.03-1.95 (m,2H), 1.84 (m, 1H), 1.7 (m, 3H), 1.51-1.35 (m, 2H), 1.32 (d, 3H, J=6.84Hz).

Elemental analysis: C₇H₁₄N₂.HCl.0.33 H₂O.0.21 NH₄Cl (MW=179.84)

C H N Cl Calculated: 46.75 9.25 17.21 23.85 Found: 46.53 9.45 17.2924.25

EXAMPLE 48 3-(trifluoromethyl)cyclohexanone, oxime

A sample of 3-trifluoromethylcyclohexanone (Aldrich, 3.3 g, 20.0 mmol)was converted to the title compound by the method of EXAMPLE 24 using2.8 g (40.0 mmol) of hydroxylamine hydrochloride and 3.4 g (42.0 mmol)of NaOAc in a mixture of 30 mL of EtOH and 30 mL of water. The procedureprovided 2.9 g (80%) of the title material as a white solid.

EXAMPLE 49 hexahydro-4-(trifluoromethyl)-1H-azepin-2-one, mixture withhexahydro-6-(trifluoromethyl)-1H-azepin-2-one

A sample of the product of EXAMPLE 48 (2.3 g, 12.5 mmol) was convertedto the title compound mixture of two regioisomers by the method ofEXAMPLE 25 using 4 mL of 80% H₂SO₄. The procedure produced 795 mg (36%)of the title materials. This mixture of 80% Isomer-A was subjected toreverse phase HPLC eluting with acetonitrile/water to obtain onlyIsomer-A (330 mg).

EXAMPLE 50 hexahydro-4-(trifluoromethyl)-1H-azepin-2-one, mixture withhexahydro-6-(trifluoromethyl)-1H-azepin-2-one

A sample of 3-trifluoromethylcyclohexanone (Aldrich, 1.7 g, 10.0 mmol)was added dropwise to a stirred mixture of 12 mL of conc H₂SO₄ and 4 mLof CH₂Cl₂. To this mixture, maintained at 0-10° C., was added 0.8 g(0.12 mmol) of sodium azide portionwise over 1 hr. After the reactionhad warmed to room temperature and stirred overnight, it was poured into50 mL of ice water and the mixture was extracted with CHCl₃ (50 mL). Theorganic layer was washed with water, dried (Na₂SO₄), filtered, andconcentrated to the crude title mixture that was 63% Isomer-B. Thismaterial was subjected to reverse phase HPLC eluting withacetonitrile/water to obtain only Isomer-B (438 mg).

EXAMPLE 51 3,4,5, 6-tetrahydro-7-methoxy-5-(trifluoromethyl)-2H-azepine

The Isomer-A product of EXAMPLE 49 (457 mg, 2.5 mmol) was reacted withtrimethyloxonium tetrafluoroborate (484 mg, 3.3 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 430 mg (87%) of the titlematerial.

EXAMPLE 52 3,4,5,6-tetrahydro-7-methoxy-3-(trifluoromethyl)-2H-azepine

The Isomer-B product of EXAMPLE 50 (350 mg, 1.9 mmol) was reacted withtrimethyloxonium tetrafluoroborate (371 mg, 2.5 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 280 mg (76%) of the titlematerial.

EXAMPLE 53 hexahydro-4-(trifluoromethyl)-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 51 (240 mg, 1.2 mmol) in 7.0 mL of MeOH wasreacted with ammonium chloride (66.0 mg, 1.2 mmol) by the method ofEXAMPLE 27 to yield 265 mg (94%) of the title material.

HRMS (EI) calcd for C₇H₁₁N₂F₃ m/e 180.087, found m/e 180.087. ¹HNMR(CD₃OD): δ1.63 (m, 1H), 1.79 (m, 1H), 1.99 (m, 1H), 2.22 (m, 1H),2.63 (m, 1H), 2.86 (dt, 1H), 2.98 (dd, 1H), 3.42-3.46 (m,2H).

Elemental analysis: C₇H₁₁N₂F₃.HCl.0.125 H₂O.0.2 NH₄Cl (MW=229.59)

C H N Cl Calculated: 36.62 5.73 13.42 18.53 Found: 36.93 5.51 13.1918.41

EXAMPLE 54 hexahydro-6-(trifluoromethyl)-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 52 (77 mg, 0.39 mmol) in 3.0 mL of MeOH wasreacted with ammonium chloride (21.0 mg, 0.39 mmol) by the method ofEXAMPLE 27 to yield 83 mg (94%) of the title material.

HRMS (EI) calcd for C₇H₁₁N₂F₃ m/e 180.087, found m/e 180.087. ¹HNMR(CD₃OD): δ3.7 (m, 1H), 3.57-3.66 (m, 1H), 2.85 (ddd, 1H)₁, 2.75 (ddd,1H), 2.53 (m, 1H), 2.2 (m, 1H), 2.1 (m, 1H), 1.84 (m, 1H), 1.70 (m, 1H).

Elemental analysis: C₇H₁₁N₂F₃.HCl.0.2 H₂O+0.1 NH₄Cl (MW=225.59)

C H N Cl Calculated: 37.27 5.72 13.04 17.29 Found: 37.21 5.47 12.7216.93

EXAMPLE 55 2-ethylcyclohexanone, oxime

A sample of 2-ethylcyclohexanone (Pfaltz & Bauer, 9.5 g, 75.0 mmol) wasconverted to the title compound by the method of EXAMPLE24 using 10.4 g(150 mmol) of hydroxylamine hydrochloride and 12.6 g (153.7 mmol) ofNaOAc in a mixture of 120 mL each of EtOH and water. The procedureproduced 9.8 g (93%) of the title material as a white solid.

EXAMPLE 56 7-ethyl-hexahydro-1H-azepin-2-one, mixture with3-ethyl-hexahydro-1H-azepin-2-one

A sample of the product of EXAMPLE 55 (4.9 g, 34.3 mmol) was convertedto the title compound mixture of two regioisomers by the method ofEXAMPLE 25 using 11 mL of 80% H₂SO₄. The procedure produced 7.2 g (73%)of the title materials as a pale yellow liquid. This mixture wasseparated into its components by chromatography to yield 2.1 g ofisomer-A and 1.1 g of isomer-B.

EXAMPLE 57 2-ethyl-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The Isomer-A product of EXAMPLE 56 (938 mg, 6.65 mmol) was reacted withtrimethyloxonium tetrafluoroborate (1.28 g, 8.6 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 802 mg (78%) of the titlematerial.

EXAMPLE 58 6-ethyl-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The Isomer-B product of EXAMPLE 56 (700 mg, 5.0 mmol) was reacted withtrimethyloxonium tetrafluoroborate (955 mg, 6.4 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 613 mg (89%) of the titlematerial.

EXAMPLE 59 7-ethyl-hexahydro-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 57 (802 mg, 5.2 mmol) in 15 mL of MeOH wasreacted with ammonium chloride (225 mg, 4.2 mmol) by the method ofEXAMPLE 27 to yield 627 mg (82%) of the title material.

HRMS (EI) calcd for C₈H₁₆N₂ m/e 140.131, found m/e 140.131. ¹HNMR(CD₃OD): δ3.57-3.51 (m, 1H), 2.82-2.75 (m, 1H), 2.65-2.60 (m, 1H),2.03-1.97 (m, 2H), 1.89-1.83 (m, 1H), 1.72-1.62 (m, 3H), 1.54-1.47 (m,1H), 1.41-1.32 (m, 1H), 1.05-1.01 (t, 3H, J=7.45 HZ)).

Elemental analysis: C₈H₁₆N₂.HCl.0.1 H₂O+0.01 NH₄Cl (MW=179.03)

C H N Cl Calculated: 53.67 9.71 15.85 20.06 Found: 53.62 10.13 15.8620.02

EXAMPLE 60 3-ethyl-hexahydro-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 58 (600 mg, 3.9 mmol) in 20 mL of MeOH wasreacted with ammonium chloride (165 mg, 3.1 mmol) by the method ofEXAMPLE 27 to yield 512 mg (93%) of the title material.

HRMS (EI) calcd for C₈H₁₆N₂ m/e 140.131, found m/e 140.132. ¹HNMR(CD3OD): δ3.48-3.30 (m, 2H), 2.76-2.74 (m, 1H), 1.90-1.71 (m, 4H),1.70-1.64 (m, 4H), 1.05-1.02 (m, 3H).

Elemental analysis: C₈H₁₆N₂.HCl.0.2 H₂O+0.01 NH₄Cl (MW=180.83)

C H N Cl Calculated: 53.14 9.72 15.57 19.80 Found: 52.98 10.46 15.6020.04

EXAMPLE 61 3,3-dimethylcyclohexanone, oxime

A sample of 3,3-dimethylcyclohexanone (Wiley, 18.9 g, 150.0 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 20.7 g(300.0 mmol) of hydroxylamine hydrochloride and 25.2 g (307.5 mmol) ofNaOAc in a mixture of 400 mL of EtOH and 400 mL of water. The procedureproduced 16.2 g (77%) of the title material as a pale yellow oil.

EXAMPLE 62 hexahydro-6,6-dimethyl-1H-azepin-2-one, mixture withhexahydro-4,4-dimethyl-1H-azepin-2-one

A sample of the product of EXAMPLE 61 (7.1 g, 50.0 mmol) was convertedto the title compound mixture of two regioisomers by the method ofEXAMPLE 25 using 12.5 mL of 80% H₂SO₄. The procedure produced 6.2 g(87%) of the title materials as a light brown solid. This mixture wasseparated into its components by chromatography to yield 1.4 g ofisomer-A and 1.8 g of isomer-B.

EXAMPLE 63 3,4,5,6-tetrahydro-7-methoxy-3,3-dimethyl-2H-azepine

The Isomer-A product of EXAMPLE 62 (985 mg, 7.0 mmol) was reacted withtrimethyloxonium tetrafluoroborate (1.3 g, 9.1 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 525 mg (48%) of the titlematerial.

EXAMPLE 64 3,4,5,6-tetrahydro-7-methoxy-5,5-dimethyl-2H-azepine

The Isomer-B product of EXAMPLE 62 (437 mg, 3.1 mmol) was reacted withtrimethyloxonium tetrafluoroborate (573 mg, 3.9 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 265 mg (55%) of the titlematerial.

EXAMPLE 65 hexahydro-6,6-dimethyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 63 (490 mg, 3.2 mmol) in 18 mL of MeOH wasreacted with ammonium chloride (125 mg, 2.4 mmol) by the method ofEXAMPLE 27 to yield 387 mg (69%) of the title material.

MS (EI) calcd for C₈H₁₆N₂ m/e 140.131, found m/e 140 (100%). ¹HNMR(CD₃OD): δ5.80-5.72 (m, 2H), 5.62-5.58 (m, 2H), 3.2 (s, 2H),2.68-2.63 (m, 2H), 0.95(s, 6H).

Elemental analysis: C₈H₁₆N₂.HCl (MW=176.69)

C H N Cl Calculated: 54.38 9.70 15.85 20.06 Found: 54.57 9.58 15.1719.61

EXAMPLE 66 hexahydro-4,4-dimethyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 64 (260 mg, 1.7 mmol) in 10 mL of EtOH wasreacted with ammonium chloride (88 mg, 1.7 mmol) by the method ofEXAMPLE 27 to yield 185 mg (55%) of the title material.

HRMS (EI) calcd for C₈H₁₆N₂ m/e 140.131, found m/e 140.132. ¹HNMR(CD3OD): δ3.42-3.39 (m, 2H), 2.62 (s, 2H), 1.75-1.65 (m, 4H), 1.07(s, 6H).

Elemental analysis: C₈H₁₆N₂.HCl.0.2 H₂O.0.32 NH₄Cl (MW=197.26)

C H N Cl Calculated: 48.71 9.47 16.47 23.72 Found: 48.68 9.41 16.4924.04

EXAMPLE 67 4-methylcyclohexanone, oxime

A sample of 4-methylcyclohexanone (Aldrich, 5.0 g, 44.6 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 4.6 g(66.9 mmol) of hydroxylamine hydrochloride and 6.2 g (75.8 mmol) ofNaOAc in a mixture of 25 mL of EtOH and 25 mL of water. The procedureproduced 4.8 g (84%) of the title material as a pale yellow oil.

EXAMPLE 68 hexahydro-5-methyl-1H-azepin-2-one

A sample of the product of EXAMPLE 67 (4.0 g, 31.4 mmol) was convertedto the title compound by the method of EXAMPLE 25 using 10 mL of 80%H₂SO₄. The procedure produced 3.2 g (80%) of the title material as ayellow oil.

EXAMPLE 69 3,4,5,6-tetrahydro-7-methoxy-4-methyl-2H-azepine

The product of EXAMPLE 68 (2.5 g, 19.7 mmol) dissolved in 25 mL ofbenzene was dried by refluxing the mixture through a Dean-Stark trap for30 minutes. To this mixture was added dimethylsulfate (1.4 mL, 19.7mmol) and the heating was continued for an additional 17 hours. Aftercooling to room temperature, the reaction was diluted with EtOAc (50 mL)and washed with 50 mL of saturated NaHCO₃. The aqueous layer wasextracted with 2×100 mL EtOAc and the combined organic phase was dried(Na₂SO₄), filtered, and stripped of all solvent under reduced pressureto yield a mixture of two immiscible oils. The top lighter phase (1.6 g,58%) was separated and identified as the title material.

EXAMPLE 70 hexahydro-5-methyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 69 (750 mg, 5.3 mmol) in 3 mL of EtOH was reactedwith ammonium chloride (285 mg, 5.3 mmol) by the method of EXAMPLE 27 toyield 700 mg (77%) of the title material.

HRMS m/z M⁺, C₇H₁₅N₂ requires 127.124; ¹H NMR (400 MHz, CD₃OD) δ3.4-3.45(m, 2H), 2.7-2.8 (m, 1H), 1.6-1.69 (m, 1H), 1.9-2.0 (m, 1H), 1.75-1.89(m, 2H), 1.14-1.28 (m, 2H), 1 (d, 3H, J=4.2 Hz).

Elemental analysis: C₇H₁₄N₂.0.85 HCl.0.8 H₂O (MW=171.59)

C H N Cl Calculated: 48.99 9.66 16.32 17.56 Found: 49.20 8.94 16.0117.24

EXAMPLE 71 4-cyclohexylcyclohexanone, oxime

A sample of 4-cyclohexylcyclohexanone (Bader, 5.0 g, 27.7 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 2.9 g(41.6 mmol) of hydroxylamine hydrochloride and 3.9 g (47.1 mmol) ofNaOAc in a mixture of 25 mL of EtOH and 25 mL of water. The procedureproduced 5.3 g (97%) of the title material as a pale yellow oil.

EXAMPLE 72 5-cyclohexyl-hexahydro-1H-azepin-2-one

A sample of the product of EXAMPLE 71 (4.5 g, 23.0 mmol) was convertedto the title compound by the method of EXAMPLE 25 using 10 mL of 80%H₂SO₄. The procedure produced 2.1 g (47%) of the title material afterchromatography.

EXAMPLE 73 4-cyclohexyl-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The product of EXAMPLE 72 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 74 5-cyclohexyl-hexahydro-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 73 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 75 4-(1-methylethyl)cyclohexanone, oxime

A sample of 4-isopropylcyclohexanone (P & B, 3.8 g, 26.9 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 2.8 g(40.4 mmol) of hydroxylamine hydrochloride and 3.7 g (45.7 mmol) ofNaOAc in a mixture of 25 mL of EtOH and 25 mL of water. The procedureproduced 4.1 g (100%) of the title material as a clear oil.

EXAMPLE 76 hexahydro-5-(1-methylethyl)-1H-azepin-2-one

A sample of the product of EXAMPLE 75 (3.7 g, 24.2 mmol) was convertedto the title compound by the method of EXAMPLE 25 using 10 mL of 80%H₂SO₄. The procedure produced 2.4 g (63%) of the title material afterchromatography.

EXAMPLE 77 3,4,5,6-tetrahydro-7-methoxy-4-(1-methylethyl)-2H-azepine

The product of EXAMPLE 76 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 78 hexahydro-5-(1-methylethyl)-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 77 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 79 4-pentylcyclohexanone, oxime

A sample of 4-n-pentylcyclohexanone (TCI, 5.2 g, 31.0 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 3.2 g(46.7 mmol) of hydroxylamine hydrochloride and 4.3 g (52.8 mmol) ofNaOAc in a mixture of 25 mL of EtOH and 25 mL of water. The procedureproduced 6.1 g (96%) of the title material as a pale yellow liquid.

EXAMPLE 80 hexahydro-5-pentyl-1H-azepin-2-one

A sample of the product of EXAMPLE 79 (5.7 g, 31.4 mmol) was convertedto the title compound by the method of EXAMPLE 25 using 20 mL of 80%H₂SO₄. The procedure produced 3.7 g (64%) of the title material afterchromatography.

EXAMPLE 81 3,4,5,6-tetrahydro-7-methoxy-4-pentyl-2H-azepine

The product of EXAMPLE 80 (1.5 g, 8.2 mmol) was reacted withtrimethyloxonium tetrafluoroborate (1.4 g, 9.8 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 1.1 g (65%) of the titlematerial.

EXAMPLE 82 hexahydrohydro-5-pentyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 81 (755 mg, 3.8 mmol) in 7.5 mL of EtOH wasreacted with ammonium chloride (204 mg, 3.8 mmol) by the method ofEXAMPLE 27 to yield 643 mg (73%) of the title material.

HRMS (EI) calcd for C₁₁H₂₂N₂ m/e 182.178, found m/e 182.179.

¹H NMR (400 MHz, D₂O) 83.35-3.53 (m, 2H), 2.6-2.75 (m, 2H), 1.96-2.04(m, 1H), 1.85-1.95 (m, 1H), 1.6-1.75 (m, 1H), 1.2-1.4 (m, 10H), 0.88 (t,3H, J=4 Hz).

Elemental analysis: C₁₁H₂₂N₂.1.0 HCl.0.2 H₂O.0.15 NH₄Cl (MW=230.40)

C H N Cl Calculated: 57.31 10.56 13.06 17.68 Found: 57.55 10.53 13.2317.69

EXAMPLE 83 4-(1,1-dimethylethyl)-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

A sample of 4-tertbutylcaprolactam (Bader, 2.5 g, 14.8 mmol) was reactedwith dimethylsulfate (1.4 mL, 14.8 mmol) by the method of EXAMPLE 69 toyield, after chromatography, 2.7 g of the title material.

EXAMPLE 84 5-(1,1-dimethylethyl)-hexahydro-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 83 (2.5 g, 13.6 mmol) in 50 mL of EtOH wasreacted with ammonium chloride (730 mg, 13.6 mmol) by the method ofEXAMPLE 27 to yield 2.2 g (78%) of the title material.

¹H NMR (400 MHz, CD₃OD) δ63.5 (ddd, 1H, J=1.87,6.08,15.0 Hz), 3.33-3.41(m, 1H), 2.66-2.71 (m, 2H), 2.13-2.21 (m, 1H), 2.0-2.08 (m, 1H), 1.39(tt, 1H, J 2.9,11.9 Hz), 1.15-1.26 (m, 2H), 0.9 (s, 9H).

Elemental analysis: C₁₀H₂₀N₂.0.8 HCl.1.125 H₂O.0.6 NH₄Cl (MW=249.80)

C H N Cl Calculated: 47.65 10.28 14.45 19.69 Found: 47.75  9.76 14.2219.97

EXAMPLE 85 3R-methylcyclohexanone, oxime

A sample of R(+)-3-methylcyclohexanone (Aldrich, 5.0 g, 44.6 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 4.6 g(66.9 mmol) of hydroxylamine hydrochloride and 6.2 g (75.8 mmol) ofNaOAc in a mixture of 25 mL of EtOH and 25 mL of water. The procedureproduced 5.7 g (100%) of the title material as a clear oil.

EXAMPLE 86 hexahydro-4R-methyl-1H-azepin-2-one, mixture withhexahydro-6R-methyl-1H-azepin-2-one

A sample of the product of EXAMPLE 85 (5.0 g, 39.3 mmol) was convertedto the title compound mixture of two regioisomers by the method ofEXAMPLE 25 using 10 mL of 80% H₂SO₄. The procedure produced 4.3 g of thetitle materials as a pale yellow oil. This mixture was separated intoits components by chromatography to yield 215 mg of isomer-A and 318 mgof isomer-B.

EXAMPLE 87 3,4,5,6-tetrahydro-7-methoxy-5R-methyl-2H-azepine

The Isomer-A product of EXAMPLE 86 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to generate the titlematerial.

EXAMPLE 88 3,4,5,6-tetrahydro-7-methoxy-3R-methyl-2H-azepine

The Isomer-B product of EXAMPLE 86 (225 mg, 1.8 mmol) was reacted withtrimethyloxonium tetrafluoroborate (340 mg, 2.3 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 900 mg of the crude titlematerial.

EXAMPLE 89 hexahydro-4R-methyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 87 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 90 hexahydro-6R-methyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 88 (250 mg, 1.8 mmol) in 10 mL of MeOH wasreacted with ammonium chloride (80 mg, 1.5 mmol) by the method ofEXAMPLE 27 to yield 155 mg (44%) of the title material.

¹H NMR (300 MHz, D₂O) δ3.22-3.36 (m, 2H), 2.58-2.72 (m, 2H), 1.89-1.94(m, 2H), 1.75-1.79 (m, 1H), 1.59-1.66 (m, 1H), 1.44-1.50 (m, 1H), 0.92(d, 3H, J=4.2 Hz).

Elemental analysis: C₇H₁₄N₂.1.0 HCl.0.25 H₂O.0.55 NH₄Cl (MW=196.60)

C H N Cl Calculated: 42.77 9.08 18.17 27.95 Found: 43.07 9.04 18.4228.37

EXAMPLE 91 2-cyclohexylcyclohexanone, oxime

A sample of 2-cyclohexylcyclohexanone (Fluka, 10.0 g, 55.5 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 5.8 g(69.5 mmol) of hydroxylamine hydrochloride and 7.7 g (82.0 mmol) ofNaOAc in a mixture of 50 mL of EtOH and 50 mL of water. The procedureproduced 11.7 g of the crude title compound as pale yellow oil.

EXAMPLE 92 3-cyclohexyl-hexahydro-1H-azepin-2-one, mixture with7-cyclohexyl-hexahydro-1H-azepin-2-one

The product of EXAMPLE 91 (10.0 g, 51.2 mmol) was converted to the titlecompound mixture of two regioisomers by the method of EXAMPLE 29 using9.13 g (51.7 mmol) of benzene sulfonylchloride. The crude productmixture was triturated with Et₂O to give 4.9 g of title product IsomerB. The filtrate was concentrated to provide a mixture of isomers butpredominately title product Isomer A. This mixture is separated into itsIsomer-A and Isomer-B components by chromatography.

EXAMPLE 93 6-cyclohexyl-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The Isomer-A product of EXAMPLE 92 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 94 2-cyclohexyl-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The Isomer-B product of EXAMPLE 92 (1.50 g, 3.6 mmol) was reacted withtrimethyloxonium tetrafluoroborate (1.48 g, 10.0 mmol) by the method ofEXAMPLE 26 to yield 0.76 g (48%) of the title material as a clearliquid.

EXAMPLE 95 3-cyclohexyl-hexahydro-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 93 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 96 7-cyclohexyl-hexahydro-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 94 (730 mg, 3.45 mmol) in 30 mL of MeOH wasreacted with ammonium chloride (177 mg, 3.31 mmol) by the method ofEXAMPLE 27 to yield 579 mg (75%) of the title material.

¹H NMR (400 MHz, D₂O) δ3.48-3.41 (dd, J=9.3 Hz, 1H), 2.8-2.7 (m, 1H),2.61-2.54 (m, 1H), 2.0-1.0 (m, 17H).

Elemental analysis: C₁₂H₂₂N₂.1.0 HCl.0.6 H₂O (MW=241.59)

C H N Cl Calculated: 59.66 10.10 11.60 14.67 Found: 59.41  9.92 11.3114.83

EXAMPLE 97 2-(1,1-dimethylethyl)cyclohexanone, oxime

A sample of 2-tert-butylcyclohexanone (Aldrich, 5.0 g, 32.4 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 3.4 g(48.6 mmol) of hydroxylamine hydrochloride and 4.5 g (55.0 mmol) ofNaOAc in a mixture of 50 mL of EtOH and 50 mL of water. The procedureproduced 5.0 g (92%) of the crude title compound.

EXAMPLE 98 3-(1,1-dimethylethyl)-hexahydro-1H-azepin-2-one, mixture with7-(1,1-dimethylethyl)-hexahydro-1H-azepin-2-one

A sample of the product of EXAMPLE 97 (4.7 g, 27.8 mmol) was convertedto the title compound mixture of two regioisomers by the method ofEXAMPLE 25 using 9 mL of 80% H₂SO₄. The procedure produced 3.9 g of thetitle materials as a yellow solid. This mixture was separated into itscomponents by chromatography to yield 832 mg of Isomer-A and 2.52 g ofIsomer-B.

EXAMPLE 99 6-(1,1-dimethylethyl)-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The Isomer-A product of EXAMPLE 98 (664 mg, 3.9 mmol) was reacted withtrimethyloxonium tetrafluoroborate (696 mg, 4.7 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 654 mg (91%) of the titlematerial.

EXAMPLE 1002-(1,1-dimethylethyl)-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The Isomer-B product of EXAMPLE 98 (352 mg, 2.1 mmol) was reacted withtrimethyloxonium tetrafluoroborate (370 mg, 2.5 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, the title material.

EXAMPLE 101 3-(1,1-dimethylethyl)-hexahydro-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 99 (551 mg, 2.7 mmol) in 10 mL of MeOH wasreacted with ammonium chloride (145 mg, 2.7 mmol) by the method ofEXAMPLE 27 to yield 350 mg of the crude title material.

EXAMPLE 102 7-(1,1-dimethylethyl)-hexahydro-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 100 (174 mg, 1.0 mmol) in 10 mL of EtOH wasreacted with ammonium chloride (51 mg, 1.0 mmol) by the method ofEXAMPLE 27 to yield the crude title material.

EXAMPLE 103 2-(2-propenyl)cyclohexanone, oxime

A sample of 2-allylcyclohexanone (Frinton, 2.0 g, 14.5 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 1.5 g(21.7 mmol) of hydroxylamine hydrochloride and 2.0 g (24.6 mmol) ofNaOAc in a mixture of 25 mL of EtOH and 25 mL of water. The procedureproduced 2.6 g of the crude title compound.

EXAMPLE 104 hexahydro-3-(2-propenyl)-1H-azepin-2-one, mixture withhexahydro-7-(2-propenyl)-1H-azepin-2-one

The title product of EXAMPLE 103 (2.0 g, 13.0 mmol) in 15 mL of acetonecontaining 1N NaOH (14.3 mL, 52.4 mmol) was reacted with benzenesulfonylchloride (2.3 g, 13.1 mmol) by the method described in EXAMPLE29. The crude reaction mixture was separated into its Isomer-A andIsomer-B components by silica gel chromatography.

EXAMPLE 105 3,4,5,6-tetrahydro-7-methoxy-6-(2-propenyl)-2H-azepine

The Isomer-A product of EXAMPLE 104 (130 mg, 0.85 mmol) was reacted withtrimethyloxonium tetrafluoroborate (163 mg, 1.10 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 91 mg (64%) of the titlematerial.

EXAMPLE 106 3,4,5,6-tetrahydro-7-methoxy-2-(2-propenyl)-2H-azepine

The Isomer-B product of EXAMPLE 104 (250 mg, 1.63 mmol) was reacted withtrimethyloxonium tetrafluoroborate (312 mg, 2.11 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 194 mg (71%) of the titlematerial.

EXAMPLE 107 hexahydro-3-(2-propenyl)-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 105 (90 mg, 0.54 mmol) in 10 mL of MeOH wasreacted with ammonium chloride (24.5 mg, 0.46 mmol) by the method ofEXAMPLE 27 to yield 68 mg (67%) of the title material.

¹H NMR (300 MHz, CD₃OD) δ5.9-5.7 (m, 1H), 5.3-5.1 (m, 2H), 3.6-3.4 (m,2H), 3.0-2.9 (m, 1H), 2.7-2.5 (m, 1H), 2.45-2.3 (m, 1H), 2.0-1.6 (M,6H).

EXAMPLE 108 hexahydro-7-(2-propenyl)-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 106 (70 mg, 0.42 mmol) in 3 mL of MeOH wasreacted with ammonium chloride (21.4 mg, 0.4 mmol) by the method ofEXAMPLE 27 to yield 60 mg (76%) of the title material.

¹H NMR (400 MHz, D₂O) δ5.9-5.8 (m, 1H), 5.26-5.19 (m, 2H), 3.79-3.70 (m,1H), 2.8-2.7 (m, 1H), 2.62-2.56 (m, 1H), 2.42-2.39 (m, 2H), 2.04-1.94(m, 2H,), 1.91-1.84 (m, 1H), 1.7-1.6 (m, 1H), 1.56-1.35 (m, 2H).

Elemental analysis: C₉H₁₆N₂.1.0 HCl.0.75 H₂O.0.05 NH₄Cl (MW=204.88)

C H N Cl Calculated: 52.76 9.20 14.01 18.17 Found: 53.13 9.06 14.0518.32

EXAMPLE 109 2-propylcyclohexanone, oxime

A sample of 2-n-propylcyclohexanone (Farchan, 19.7 g, 140.5 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 14.6 g(211.0 mmol) of hydroxylamine hydrochloride and 20.8 g (252.9 mmol) ofNaOAc in a mixture of 150 mL of EtOH and 100 mL of water. The procedureproduced 23.4 g of the crude title compound.

EXAMPLE 110 hexahydro-3-propyl-1H-azepin-2-one, mixture withhexahydro-7-propyl-1H-azepin-2-one

The product of EXAMPLE 109 (11.5 g, 74.1 mmol) was converted to thetitle compound mixture of two regioisomers by the method of EXAMPLE 29using 13.2 g (74.5 mmol) of benzene sulfonylchloride. The crude paleyellow solid product mixture (6.1 g) was separated into its Isomer-A andIsomer-B components by chromatography.

EXAMPLE 111 3,4,5,6-tetrahydro-7-methoxy-6-propyl-2H-azepine

The Isomer-A product of EXAMPLE 110 (0.50 g, 3.2 mmol) was reacted withtrimethyloxonium tetrafluoroborate (0.62 g, 4.2 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 0.45 g (83%) of the titlematerial.

Elemental analysis: C₁₀H₁₉NO.0.1 H₂O (MW=169.27)

C H N Calculated: 70.21 11.31 8.19 Found: 70.35 11.32 7.97

EXAMPLE 112 3,4,5,6-tetrahydro-7-methoxy-2-propyl-2H-azepine

The Isomer-B product of EXAMPLE 110 (0 65 g, 4.2 mmol) was reacted withtrimethyloxonium tetrafluoroborate (0.81 g, 5.4 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 0.60 g (84%) of the titlematerial.

Elemental analysis: C₁₀H₁₉NO.0.125 H₂O (MW=171.52)

C H N Calculated: 70.03 11.31 8.47 Found: 69.94 11.41 7.92

EXAMPLE 113 hexahydro-3-propyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 111 (415 mg, 2.45 mmol) in 20 mL of MeOH wasreacted with ammonium chloride (111 mg, 2.1 mmol) by the method ofEXAMPLE 27 to yield 360 mg (76%) of the title material.

¹H NMR (400 MHz, CD₃OD) δ3.48 (m, 2H), 2.90-2.81 (m, 1H), 1.96-1.85 (m,1H), 1.85-1.55 (m, 7H), 1.55-1.32 (m, 2H), 1.00 (t, 3H, J=7.3 Hz).

Elemental analysis: C₉H₁₈N₂.1.0 HCl.0.15 H₂O.0.02 NH₄Cl (MW=194.43)

C H N Cl Calculated: 55.60 10.02 14.55 18.60 Found: 55.57  9.92 14.3518.62

EXAMPLE 114 hexahydro-7-propyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 112 (560 mg, 3.3 mmol) in 20 mL of MeOH wasreacted with ammonium chloride (150 mg, 2.8 mmol) by the method ofEXAMPLE 27 to yield 514 mg (78%) of the title material.

¹H NMR (400 MHz, CD₃OD) δ83.68-3.58 (m, 1H), 2.79 (ddd, 1H, J=14.3,12.2, 1.9 Hz), 2.61 (dd, 1H, J=14.6, 6.6 Hz), 2.06-1.95 (m, 2H),1.90-1.81 (m, 1H), 1.75-1.32 (m, 7H), 0.98 (t, 3H, J=7.2 Hz).

Elemental analysis: C₉H₁₈N₂.1.0 HCl.0.4 H₂O.0.05 NH₄Cl (MW=200.60)

C H N Cl Calculated: 53.89 10.05 14.31 18.56 Found: 53.95 10.15 13.9618.64

EXAMPLE 115 2-(1-methylpropyl)cyclohexanone, oxime

A sample of 2-sec-butylcyclohexanone (Lancaster, 9.9 g, 64.2 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 6.7 g(96.3 mmol) of hydroxylamine hydrochloride and 9.5 g (115.6 mmol) ofNaOAc in a mixture of 75 mL of EtOH and 50 mL of water. The procedureproduced 11.3 g of the crude title compound.

EXAMPLE 116 hexahydro-3-(1-methylpropyl)-1H-azepin-2-one, mixture withhexahydro-7-(1-methylpropyl)-1H-azepin-2-one

The product of EXAMPLE 115 is converted to the title compound mixture oftwo regioisomers by the method of EXAMPLE 25 using 80% H₂SO₄. Thisproduct mixture is separated into its Isomer-A and Isomer-B componentsby chromatography.

EXAMPLE 117 3,4,5,6-tetrahydro-7-methoxy-6-(1-methylpropyl)-2H-azepine

The Isomer-A product of EXAMPLE 116 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 118 3,4,5,6-tetrahydro-7-methoxy-2-(1-methylpropyl)-2H-azepine

The Isomer-B product of EXAMPLE 116 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 119 hexahydro-3-(1-methylpropyl)-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 117 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 120 hexahydro-7-(1-methylpropyl)-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 118 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 121 3,4-dimethylcyclohexanone, oxime

A sample of 3,4-dimethylcyclohexanone (TCI, 9.0 g, 71.0 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 7.4 g(107.0 mmol) of hydroxylamine hydrochloride and 9.9 g (121.0 mmol) ofNaOAc in a mixture of 50 mL of EtOH and 50 mL of water. The procedureyielded 2.6 g of the crude title compound.

EXAMPLE 122 hexahydro-4,5-dimethyl-1H-azepin-2-one, mixture withhexahydro-5,6-dimethyl-1H-azepin-2-one

A sample of the product of EXAMPLE 121 (8.0 g, 56.6 mmol) was convertedto the title compound mixture of two regioisomers by the method ofEXAMPLE 25 using 20 mL of 80% H₂SO₄. The procedure gave 7.1 g of thetitle materials as an amber liquid. This mixture was separated into itscomponent regioisomers by chromatography to yield 233 mg of Isomer-Atitle compound and 87 mg of Isomer-B title compound.

EXAMPLE 123 3,4,5,6-tetrahydro-7-methoxy-4,5-dimethyl-2H-azepine

The Isomer-A product of EXAMPLE 122 (205 mg, 1.5 mmol) was reacted withtrimethyloxonium tetrafluoroborate (279 mg, 1.9 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 100 mg (53%) of the titlematerial.

EXAMPLE 124 3,4,5,6-tetrahydro-7-methoxy-3,4-dimethyl-2H-azepine

The Isomer-B product of EXAMPLE 122 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 125 hexahydro-4,5-dimethyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 123 (100 mg, 0.64 mmol) in 5 mL of MeOH wasreacted with ammonium chloride (29.3 mg, 547 mmol) by the method ofEXAMPLE 27 to yield 68 mg (66%) of the white solid title material.

¹H NMR (300 MHz, D₂O) δ3.25-3.45 (m, 2H), 2.85 (d, 1H, J=12 Hz), 2.6(dd, 1H, J=9, 15 Hz), 2.05-2.08 (m, 1H), 1.9-2.0 (m, 1H), 1.4-1.61 (m,2H), 0.94 (d, 3H, J=9 Hz), 0.88 (d, 3H, J=6 Hz).

Elemental analysis: C₈H₁₆N₂.1.0 HCl.0.01 H₂O.0.2 NH₄Cl (MW=187.57)

C H N Cl Calculated: 51.23 9.58 16.43 22.68 Found: 50.85 9.51 16.2222.59

EXAMPLE 126 hexahydro-5,6-dimethyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 124 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 127 2,5-dimethylcyclohexanone, oxime

A sample of 2,5-dimethylcyclohexanone (TCI, 9.0 g, 71.0 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 7.4 g(107.0 mmol) of hydroxylamine hydrochloride and 9.9 g (121.0 mmol) ofNaOAc in a mixture of 50 mL of EtOH and 50 mL of water. The proceduregenerated 7.1 g (71%) of the crude title compound.

EXAMPLE 128 hexahydro-3,6-dimethyl-1H-azepin-2-one, mixture withhexahydro-4,7-dimethyl-1H-azepin-2-one

A sample of the product of EXAMPLE 127 (6.8 g, 48.5 mmol) was convertedto the title compound mixture of two regioisomers by the method ofEXAMPLE 25 using 20 mL of 80% H₂SO₄. The procedure produced the crudetitle materials. This mixture was separated into its componentregioisomers by chromatography to yield no clean amount of Isomer-Atitle compound and 1.3 g of pure Isomer-B title compound.Rechromatography of the mixtures yields pure Isomer-A.

EXAMPLE 129 3,4,5,6-tetrahydro-7-methoxy-3,6-dimethyl-2H-azepine

The Isomer-A product of EXAMPLE 128 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 130 3,4,5,6-tetrahydro-7-methoxy-2,5-dimethyl-2H-azepine

The Isomer-B product of EXAMPLE 128 (1.0 g, 7.1 mmol) was reacted withtrimethyloxonium tetrafluoroborate (1.3 g, 8.5 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 700 mg of the title material.

EXAMPLE 131 hexahydro-3,6-dimethyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 129 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 132 hexahydro-4,7-dimethyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 130 (250 mg, 1.6 mmol) in 2.5 mL of EtOH wasreacted with ammonium chloride (86.0 mg, 1.6 mmol) by the method ofEXAMPLE 27 to yield 220 mg (75%) of the white solid title material.

¹H NMR (400 MHz, D₂O) δ3.7-3.8 (m, 1H,), 2.7 (dd, 1H, J=10,12 Hz), 2.4(d, 1H, J=15 Hz), 1.9-2.0 (m, 1H), 1.7-1.85 (m, 2H), 1.4-1.55 (m, 2H),1.3 (d, 6H, J=8 Hz), 1.06 (d, 3H, J=8 Hz)

Elemental analysis: C₈H₁₆N₂.1.06 HCl.0.25 H₂O (MW=183.38)

C H N Cl Calculated: 52.40 9.65 15.28 20.49 Found: 52.10 9.82 15.9420.77

EXAMPLE 133 (2R-trans)-2-(1-methylethyl)-5-methylcyclohexanone, oxime

A sample of (−)menthone (Aldrich, 10.0 g, 64.8 mmol) was converted tothe title compound by the method of EXAMPLE 24 using 6.8 g (97.3 mmol)of hydroxylamine hydrochloride and 9.0 g (110.2 mmol) of NaOAc in amixture of 50 mL of EtOH and 50 mL of water. The procedure produced thecrude title compound.

EXAMPLE 134(4R-trans)-hexahydro-7-(1-methylethyl)-4-methyl-1H-azepin-2-one, mixturewith (3S-trans)-hexahydro-3-(1-methylethyl)-6-methyl-1H-azepin-2-one

A sample of the product of EXAMPLE 133 (10.0 g, 59.0 mmol) was convertedto the title compound mixture of two regioisomers by the method ofEXAMPLE 25 using 20 mL of 80% H₂SO₄. The procedure produced the crudetitle materials.

This mixture was separated into its component regioisomers bychromatography to yield 3.1 g of Isomer-A title compound and 1.5 g ofpure Isomer-B title compound.

EXAMPLE 135(5R-trans)-3,4,5,6-tetrahydro-7-methoxy-2-(1-methylethyl)-5-methyl-2H-azepine

The Isomer-A product of EXAMPLE 134 (1.0 g, 5.9 mmol) was reacted withtrimethyloxonium tetrafluoroborate (1.1 g, 7.1 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 740 mg (68%) of the titlematerial.

EXAMPLE 136(6R-trans)-3,4,5,6-tetrahydro-7-methoxy-6-(1-methylethyl)-3-methyl-2H-azepine

The Isomer-B product of EXAMPLE 134 (840 mg, 5.0 mmol) was reacted withtrimethyloxonium tetrafluoroborate (880 mg, 6.0 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 441 mg (49%) of the titlematerial.

EXAMPLE 137(7S-trans)-hexahydro-7-(1-methylethyl)-4-methyl-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 135 (690 mg, 3.8 mmol) in 20 mL of MeOH wasreacted with ammonium chloride (201 mg, 3.8 mmol) by the method ofEXAMPLE 27 to yield 570 mg (73%) of the white solid title material.

HRMS (EI) calcd for C₁₀H₂₀N₂ m/e 168.163, found m/e 168.163. ¹H NMR (400MHz, D₂O) δ3.4-3.5 (m, 1H), 2.7 (dd, 1H, J=12,15 Hz), 2.4 (bd, 1H, J=14Hz), 1.8-2 (m, 3H), 1.7-1.8 (m, 1H), 1.31-1.45 (m, 2H), 1.05 (d, 3H,J=7.6 Hz), 0.95 (d, 6H, J=8 Hz).

Elemental analysis: C₁₀H₂₀N₂.1.0 HCl.0.33 H₂O.0.05 NH₄Cl (MW=213.36)

C H N Cl Calculated: 56.29 10.33 13.46 17.45 Found: 56.28 10.81 13.5717.58

EXAMPLE 138(3S-trans)-hexahydro-3-(1-methylethyl)-6-methyl-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 136 (300 mg, 1.6 mmol) in 10 mL of MeOH wasreacted with ammonium chloride (70 mg, 1.3 mmol) by the method ofEXAMPLE 27 to yield 240 mg (86%) of the white solid title material.

[α]_(D)=+33.6° (0.53, CH₃OH)

¹H NMR (400 MHz, D₂O) δ3.6 (bd, 1H, J=14 Hz), 3.2 (dd, 1H, J=4,16 Hz)2.35-2.45 (m, 1H), 2.2-2.3 (m, 1H), 1.95 (m, 3H), 1.65-1.75 (m, 1H),1.42-1.52 (m, 1H), 1.0 (dd, 6H, J=7 Hz), 0.95 (d, 3H, J=6 Hz).

Elemental analysis: C₁₀H₂₀N₂.1.0 HCl.0.33 H₂O.0.05 NH₄Cl (MW=213.73)

C H N Cl Calculated: 56.20 10.45 13.11 15.76 Found: 56.58 10.24 12.7015.88

EXAMPLE 139 3R-methylcyclopentanone, oxime

A sample of R(+)-3-methylcyclopentanone (Aldrich, 5.0 g, 50.9 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 5.3 g(76.4 mmol) of hydroxylamine hydrochloride and 7.1 g (86.5 mmol) ofNaOAc in a mixture of 25 mL of EtOH and 25 mL of water. The procedureproduced 4.9 g (86%) of the title material as white solid.

EXAMPLE 140 4R-methylpiperidin-2-one, mixture with5R-methylpiperidin-2-one

A sample of the product of EXAMPLE 139 (4.5 g, 39.8 mmol) was convertedto the title compound mixture of two regioisomers by the method ofEXAMPLE 25 using 10 mL of 80% H₂SO₄. The procedure produced 4.6 g of thetitle materials. This mixture was separated into its components bychromatography to yield Isomer-A and Isomer-B.

EXAMPLE 141 2,3,4,5-tetrahydro-6-methoxy-4R-methylpyridine

The Isomer-A product of EXAMPLE 140 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 142 2,3,4,5-tetrahydro-6-methoxy-3R-methylpyridine

The Isomer-B product of EXAMPLE 140 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 143 4R-methylpiperidin-2-imine, monohydrochloride

The product of EXAMPLE 141 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 144 5R-methylpiperidin-2-imine, monohydrochloride

The product of EXAMPLE 142 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 145 3-ethylcyclopentanone, oxime

A sample of 3-ethylcyclopentanone is converted to the title compound bythe method of EXAMPLE 24 using hydroxylamine hydrochloride and NaOAc ina mixture of EtOH and water.

EXAMPLE 146 4-ethylpiperidin-2-one, mixture with 5-ethylpiperidin-2-one

The product of EXAMPLE 145 is converted to the title compound mixture oftwo regioisomers by the method of EXAMPLE 25 using 80% H₂SO₄. Thisproduct mixture is separated into its Isomer-A and Isomer-B componentsby chromatography.

EXAMPLE 147 4-ethyl-2,3,4,5-tetrahydro-6-methoxypyridine

The Isomer-A product of EXAMPLE 146 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 148 3-ethyl-2,3,4,5-tetrahydro-6-methoxypyridine

The Isomer-B product of EXAMPLE 146 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 149 4-ethylpiperidin-2-imine, monohydrochloride

The product of EXAMPLE 147 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 150 5-ethylpiperidin-2-imine, monohydrochloride

The product of EXAMPLE 148 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 151 2-ethylcyclopentanone, oxime

A sample of 2-ethylcyclopentanone (P & B, 9.8 g, 87.5 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 8.5 g(122.5 mmol) of hydroxylamine hydrochloride and 12.9 g (157.5 mmol) ofNaOAc in a mixture of 90 mL of EtOH and 90 mL of water. The procedureproduced 12.0 g of the crude title compound as a yellow oil.

EXAMPLE 152 6-ethylpiperidin-2-one, mixture with 3-ethylpiperidin-2-one

The product of EXAMPLE 151 (2.1 g, 16.4 mmol) was converted to the titlecompound mixture of two regioisomers by the method of EXAMPLE 29 using2.9 g (16.4 mmol) of benzene sulfonylchloride. The crude pale yellowsolid product mixture (2.3 g) was separated into its Isomer-A andIsomer-B components by chromatography.

EXAMPLE 153 2-ethyl-2,3,4,5-tetrahydro-6-methoxypyridine

The Isomer-A product of EXAMPLE 152 (280 mg, 2.2 mmol) was reacted withtrimethyloxonium tetrafluoroborate (425 mg, 2.9 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 300 mg (96%) of the titlematerial as a crystaline solid.

EXAMPLE 154 3-ethyl-3,4,5,6-tetrahydro-2-methoxypyridine

The Isomer-B product of EXAMPLE 152 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 155 6-ethylpiperidin-2-imine, monohydrochloride

The product of EXAMPLE 153 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 156 3-ethylpiperidin-2-imine, monohydrochloride

The product of EXAMPLE 154 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 157 2,2-dimethylcyclopentanone, oxime

A sample of 2,2-dimethylcyclopentanone (Aldrich, 9.0 g, 80.0 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 7.8 g(112.0 mmol) of hydroxylamine hydrochloride and 11.8 g (144.0 mmol) ofNaOAc in a mixture of 90 mL of EtOH and 90 mL of water. The procedureproduced 13.1 g of the crude title compound as a colorless oil.

EXAMPLE 158 6,6-dimethylpiperidin-2-one, mixture with3,3-dimethylpiperidin-2-one

The product of EXAMPLE 157 (13.3 g, 104.7 mmol) was converted to thetitle compound mixture of two regioisomers by the method of EXAMPLE 29using 18.5 g (104.7 mmol) of benzene sulfonylchloride. The crude paleyellow solid product mixture (8.3 g) was separated into its Isomer-A andIsomer-B components by chromatography.

EXAMPLE 159 2,3,4,5-tetrahydro-6-methoxy-2,2-dimethylpyridine

The Isomer-A product of EXAMPLE 158 (880 mg, 6.9 mmol) was reacted withtrimethyloxonium tetrafluoroborate (1.3 g, 9.0 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 502 mg (51%) of the titlematerial as a pale yellow solid.

EXAMPLE 160 3,4,5,6-tetrahydro-2-methoxy-3,3-dimethylpyridine

The Isomer-B product of EXAMPLE 158 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 161 6,6-dimethylpiperidin-2-imine, monohydrochloride

The product of EXAMPLE 159 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 162 3,3-dimethylpiperidin-2-imine, monohydrochloride

The product of EXAMPLE 160 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 163 3,4-dihydro-2-methoxyquinoline

A sample of 3,4-dihydrocarbostyril (Apin Chemicals Ltd., 736 mg, 5.0mmol) was reacted with trimethyloxonium tetrafluoroborate (924 mg, 6.2mmol) by the method of EXAMPLE 26 to yield, after chromatography, 130 mg(16%) of the title material.

EXAMPLE 164 1,2,3,4-tetrahydroquinolin-2-imine, monohydrochloride

The product of EXAMPLE 163 (98 mg, 0.61 mmol) in 10 mL of MeOH and 10 mLof CH₂Cl₂ was reacted with ammonium chloride (27 mg, 0.52 mmol) by themethod of EXAMPLE 27 to yield 57 mg (47%) of the title material.

HRMS m/z M⁺ 147.086; C₉H₁₁N₂ requires 147.092.

IR (KBr): ¹H NMR(D₂O): δ7.37-7.30 (m, 2H), 7.25 (m, 1H), 7.10 (m, 1H),3.00 (m, 2H), 2.93 (m, 2H)

Elemental analysis: C₉H₁₀N₂.1.0 HCl.0.2 H₂O.1.0 NH₄Cl (MW=240.65).

C H N Cl Calculated: 44.92 6.49 17.46 29.46 Found: 44.94 6.48 17.5829.60

EXAMPLE 165 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

A sample of alpha tetralone (Aldrich, 36.5 g, 0.25 mol) was converted tothe title material by the method of EXAMPLE 50 using 19.5 g (0.3 mol) ofsodium azide in a mixture of 300 mL of conc H₂SO₄ and 100 mL of CH₂Cl₂.This procedure yielded after recrystalization from EtOH 12.1 g (30%) ofthe title product.

EXAMPLE 166 4,5-dihydro-2-methoxy-3H-1-benzazepine

A sample of the title compound of EXAMPLE 165 (3.2 g, 20.0 mmol) wasreacted with trimethyloxonium tetrafluoroborate (4.4 g, 30.0 mmol) bythe method of EXAMPLE 26 to yield, after chromatography, 2.5 g (73%) ofthe title material.

EXAMPLE 167 2,3,4,5-tetrahydro-1H-1-benzazepin-2-imine,monohydrochloride

The product of EXAMPLE 166 (1.9 g, 11.1 mmol) in 15 mL of MeOH and 10 mLof CH₂Cl₂ was reacted with ammonium chloride (413 mg, 7.8 mmol) by themethod of EXAMPLE 27 to yield 1.4 g (88%) of the title material.

HRMS m/z M⁺ 161.103; C₁₀H₁₃N₂ requires 161.108.

¹H NMR(D₂O): δ87.44-7.32 (m, 3H), 7.2 (m, 1H), 2.81 (m, 2H), 2.50 (m,2H), 2.34 (m, 2H).

Elemental analysis: C₁₀H₁₂N₂.1.0 HCl.0.33 H₂O (MW=202.63).

C H N Cl Calculated: 59.28 6.80 14.24 17.50 Found: 59.30 6.68 13.9017.41

EXAMPLE 168 4,4-dimethylpiperidin-2-one

A solution of 3,3-dimethylglutaric anhydride (10 g, 70 mmol) in ammoniumhydroxide (conc., 30 mL) was hydrogenated over Pd/Al₂O₃ at 1600 psi and250° C. for 3 h. The flask was cooled to RT and treated with brine(satd., 75 mL) followed by extraction with CH₂Cl₂ (150 mL), dried(Na₂SO₄) and evaporated to yield a solid, that was purified bychromatography to yield 1.4 g (16%) of the title material.

IR (KBr): 3260, 2949, 1655, 1626, 1502, 1338

¹H NMR(CDCl₃): δ5.98 (br s, 1H), 3.38-3.32 (m, 2H), 2.13 (s, 2H), 1.59(t, J=5 Hz, 2H), 1.05 (s, 6H)

Elemental analysis: C₇H₁₃NO.0.02 CHCl₃ (MW=127.19).

C H N Calculated: 65.07 10.13 10.81 Found: 65.20 9.74 10.78

EXAMPLE 169 2,3,4,5-tetrahydro-4,4-dimethyl-6-methoxypyridine

A sample of the title compound of EXAMPLE 168 (636 mg, 5 mmol) wasreacted with trimethyloxonium tetrafluoroborate (890 mg, 6 mmol) by themethod of EXAMPLE 26 to yield, after chromatography, 550 mg (78%) of thetitle material.

EXAMPLE 170 4,4-dimethylpiperidin-2-imine, monohydrochloride

The product of EXAMPLE 169 (550 mg, 3.9 mmol) in 25 mL of MeOH wasreacted with ammonium chloride (178 mg, 3.3 mmol) by the method ofEXAMPLE 27 to yield 460 mg (86%) of the title material.

DSC: 167.65° C.; MS (EI) m/e, 126 (100%, M.).

IR (KBr): 3294, 3148, 3009, 2945, 1687; ¹H NMR(DMSO d₆-D₂O exchange):83.33 (t, J=5 Hz, 2H), 2.34 (s, 2H), 1.60 (t, J=5 Hz,, 2H), 1.00 (S, 6H)

Elemental analysis: C₇H₁₄N₂.1.0 HCl.0.2 H₂O.0.2 NH₄Cl (MW=176.97).

C H N Cl Calculated: 47.51 9.23 17.41 24.04 Found: 47.13 9.05 17.7624.31

EXAMPLE 171 (trans)-octahydro-1H-isoindol-1-one

A solution of trans-1,2-cyclohexanedicarboxylic anhydride (10 g, 65mmol) in ammonium hydroxide (conc., 30 mL) was hydrogenated by themethod of EXAMPLE 168 to yield 7.4 g (80%) of the title material.

mp: 85-88° C.; ¹H NMR(CDCl₃): δ6.47 (br s, 1H), 3.42-3.31 (m, 1H),3.00-2.93 (m, 1H), 2.50-2.35 (m, 1H), 2.07-1.15 (m, 9H).

EXAMPLE 172 (trans)-3a,4,5,6,7,7a-hexahydro-3-methoxy-1H-isoindole

A sample of the title compound of EXAMPLE 171 (1.39 g, 10 mmol) wasreacted with trimethyloxonium tetrafluoroborate (1.78 g, 12 mmol) by themethod of EXAMPLE 26 to yield, after chromatography, 1.05 g (69%) of thetitle material.

EXAMPLE 173 (trans)-octahydro-2H-isoindol-1-imine, monohydrochloride

The product of EXAMPLE 172 (1.04 g, 6.79 mmol) in 50 mL of MeOH wasreacted with ammonium chloride (359 mg, 6.70 mmol) by the method ofEXAMPLE 27 to yield 940 mg (75%) of the title material.

IR (KBr): 3400-2700, 1686 cm⁻¹; ¹H NMR(DMSO d₆-D₂O exchange): δ3.52-3.45(m, 1H), 3.28-3.22 (m, 1H), 3.04-2.98 (m, 1H), 2.51-2.43 (m, 1H),1.90-1.20 (m, 8H).

Elemental analysis: C₈H₁₄N₂.1.0 HCl.0.25 H₂O0.25 NH₄Cl (MW=192.55).

C H N Cl Calculated: 49.90 8.64 16.37 23.02 Found: 50.00 8.27 16.2823.09

EXAMPLE 174 bicyclo[2.2.1]heptan-2-one, oxime

Norcamphor (11 g, 100 mmol) was reacted with hydroxylamine hydrochloride(13.2 g) and sodium acetate (13.1 g) by the method of EXAMPLE 173 toyield, 11.5 g (96%) of the title material.

EXAMPLE 175 2-azabicyclo[3.2.1]octan-3-one, mixture with3-azabicyclo[3.2.1]octan-2-one

The product of EXAMPLE 174 (10 g, 80 mmol) was converted to the titlecompound mixture of two regioisomers by the method of EXAMPLE 25 using80% H₂SO₄. This product mixture was purified by chromatography but notseparated into its Isomer-A and Isomer-B components to yield 835 mg(8%), as a clear liquid.

EXAMPLE 176 3-methoxy-2-azabicyclo[3.2.1]oct-2-ene, mixture with2-methoxy-3-azabicyclo[3.2.1]oct-2-ene

A sample of the title compounds of EXAMPLE 175 (650 mg, 5 mmol) wasreacted with trimethyloxonium tetrafluoroborate (890 g, 6 mmol) by themethod of EXAMPLE 26 to yield, after chromatography, 550 mg (80%) of thetitle materials.

EXAMPLE 177 2-azabicyclo[3.2.1]octan-3-imine, monohydrochloride, mixturewith 3-azabicyclo[3.2.1]octan-2-imine, monohydrochloride

The products of EXAMPLE 176 (530 mg, 3.9 mmol) in 25 mL of MeOH werereacted with ammonium chloride (178 mg, 3.3 mmol) by the method ofEXAMPLE 27 to yield 400 mg (67%) of the title materials.

MS (EI) m/e;124 (90%, M.), 83 (100%)

¹H NMR(DMSO d₆-D₂O exchange): δ3.44-3.37 (m, 1H), 3.19-3.11(m, 1H),2.95-2.89 (m, 1H), 2.57-2.50 (m, 2H), 2.07-1.52 (m, 5H).

Elemental analysis: C₈H₁₄N₂.1.08 HCl.0.75 H₂O.0.4 NH₄Cl (MW=212.500).

C H N Cl Calculated: 42.36 8.22 16.94 26.44 Found: 42.70 8.27 17.0326.65

EXAMPLE 178 2,2,2-trichloro-N-(2-propenyl)acetamide

To a stirred solution of allylamine (5 g, 88 mmol) and triethylamine(9.6 g, 95 mmol) in CH₂Cl₂ (200 mL) at −10° C. was added trichloroacetylchloride (16.7 g, 92 mmol). The resulting solution was allowed togradually warm to RT and stir for 24 h. The reaction solution wasextracted with brine (satd., 100 mL) and dried (Na₂SO₄) to yield 17 g(96%) of the title compound as a white solid.

EXAMPLE 179 3,3-dichloro-4-(chloromethyl)pyrrolidin-2-one

To a stirred solution of the title compound EXAMPLE 178 (15 g, 74 mmol)in xylene (600 mL) under N₂ was added RuCl₂(PPh₃)₃ (696 mg (0.74 mmol),and the solution was refluxed for 2 h. The solvent was removed and theresidue was chromatographed and crystallized (EtOAc) to yield 4.5 g(30%) of the title compound as a solid.

¹H NMR(CDCl₃): δ7.40 (br s, 1H), 4.00 (dd, J=4, 12 Hz, 1H), 3.76 (dd,J=9, 12 Hz, 1H), 3.70 (dd, J=6, 8 Hz, 1H), 3.28 (dd, J=8, 9 Hz, 1H),3.12-3.23 (m, 1H).

EXAMPLE 180 4-methylpyrrolidin-2-one

A mixture of the title compound in EXAMPLE 179 (3 g, 15 mmol),tributyltin hydride (14.3 mL) and AIBN (25 mg) was heated at 140° C. for8 h. The product was chromatographed to yield 900 mg (61%) of the titlecompound as a solid.

EXAMPLE 181 3,4-dihydro-5-methoxy-3-methyl-2H-pyrrole

The product of EXAMPLE 180 (500 mg, 5 mmol) was reacted withtrimethyloxonium tetrafluoroborate (890 mg, 6 mmol) by the method ofEXAMPLE 26 to yield, after chromatography 610 mg of the title materialcontaining traces of solvent.

EXAMPLE 182 4-methylpyrrolidin-2-imine, monohydrochloride

The product of EXAMPLE 181 (610 mg, 5 mmol) in 25 mL of MeOH was reactedwith ammonium chloride (200 mg, 4 mmol) by the method of EXAMPLE 27 toyield 500 mg (70%) of the title material.

HRMS m/z M⁺ 98.0844; C₅H₁₀N₂ requires 98.0844.

Elemental analysis: C₅H₁₀N₂.HCl.0.25 H₂O.0.75 NH₄Cl (MW=179.23).

C H N Cl Calculated: 33.50 8.15 21.49 34.62 Found: 33.17 7.96 21.4034.69

EXAMPLE 183 2-butylcyclohexanone, oxime

A sample of 2-n-butylcyclohexanone (Aldrich, 10.4 g, 67.2 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 7.0 g(100.7 mmol) of hydroxylamine hydrochloride and 9.8 g (120.1 mmol) ofNaOAc in a mixture of 75 mL of EtOH and 50 mL of water. The procedureproduced 11.3 g (99%) of the crude title compound.

EXAMPLE 184 3-butylhexahydro-1H-azepin-2-one, mixture with7-butylhexahydro-1H-azepin-2-one

The product of EXAMPLE 184 (11.1 g, 65.6 mmol) was converted to thetitle compound mixture of two regioisomers by the method of EXAMPLE 29using 12.3 g (70.0 mmol) of benzene sulfonylchloride. The crude paleyellow solid product mixture (8.3 g) was separated into its Isomer-A andIsomer-B components by chromatography.

EXAMPLE 185 6-butyl-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The Isomer-A product of EXAMPLE 184 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 186 2-butyl-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The Isomer-B product of EXAMPLE 184 (0.63 g, 3.7 mmol) was reacted withtrimethyloxonium tetrafluoroborate (0.71 g, 4.8 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 0.53 g (84%) of the titlematerial.

Elemental analysis: C₁₁H₂₁NO.0.125 H₂O (MW=185.55).

C H N Calculated: 71.21 11.54 7.55 Found: 71.14 11.73 7.25

EXAMPLE 187 3-butylhexahydro-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 185 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 188 7-butylhexahydro-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 186 (500 mg, 2.7 mmol) in 20 mL of MeOH wasreacted with ammonium chloride (124 mg, 2.3 mmol) by the method ofEXAMPLE 27 to yield 425 mg (74%) of the title material.

¹H NMR (400 MHz, CD₃OD) δ3.64-3.55 (m, 1H), 2.79 (ddd, 1H, J=14.6, 6.7,1.5 Hz), 2.61 (ddt, 1H, J=14.6, 6.7, 1.5 Hz), 2.06-1.95 (m, 2H),1.90-1.81 (m, 1H), 1.76-1.55 (m, 3H), 1.55-1.31 (m, 6H), 0.95 (t, 3H,J=7.1 Hz).

Elemental analysis: C₁₀H₂₀ON₂.1.0 HCl.0.33 H₂O.0.03 NH₄Cl (MW=212.29)

C H N Cl Calculated: 56.58 10.34 13.39 17.20 Found: 56.49 10.47 12.9917.55

EXAMPLE 189 2-phenylcyclohexanone, oxime

A sample of 2-phenylcyclohexanone (Aldrich, 10.4 g, 60 mmol) wasconverted to the title compound by the method of EXAMPLE 24 using 7.2 g(104 mmol) of hydroxylamine hydrochloride and 8.4 g (102 mmol) of NaoAcin a mixture of 75 mL of EtOH and 75 mL of water. The procedure produced11.0 g (97%) of the title material as a white solid.

EXAMPLE 190 hexahydro-7-phenyl-1H-azepin-2-one

To the product of EXAMPLE 189 (10.9 g, 57.7 mmol) in 60 mL of acetonewas added 1N NaOH (64 mL, 64 mmol). After cooling this mixture in an icebath, benzene sulfonylchloride (10.6 g, 60 mmol) was added drop-wiseover 5 minutes to the stirred reaction mixture maintained under a N₂atmosphere. The reaction was allowed to warm to room temperature andstir overnight. The filtrate was concentrated and partitioned betweenEtOAc and brine. The organic layer was dried (Na₂SO₄), filtered, andstripped of all solvent under reduced pressure. A white solid was thusobtained and recrystallized from hot methyl t-butyl ether/acetone toyield 3.5 g (32%) of the title material.

EXAMPLE 191 3,4,5,6-tetrahydro-7-methoxy-2-phenyl-2H-azepine

The product of EXAMPLE 29 (1.75 g, 9.3 mmol) was reacted withtrimethyloxonium tetrafluoroborate (1.8 g, 12.0 mmol) by the method ofEXAMPLE 26 to yield 1.4 g (72%) of the title material.

EXAMPLE 192 hexahydro-7-phenyl-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 191 (1.4 g, 6.9 mmol) in 75 mL of MeOH wasreacted with ammonium chloride (0.31 g, 5.9 mmol) by the method ofEXAMPLE 27 to yield 1.2 g (77%) of the title material.

¹H NMR (CD₃OD): δ7.50-7.30 (m, 5H), 2. 98 (tt, 1H), 2.74 (dd, 1H),2.12-1.76 (m, 6H), 1.60 (m, 1H).

Elemental analysis: C₁₂H₁₆N₂.HCl.0.5 H₂O (MW=233.74)

C H N Cl Calculated: 61.66 7.76 11.98 15.17 Found: 61.69 8.15 11.4215.41

EXAMPLE 193 2-(2-ethylbutyl)cyclohexanone, oxime

A sample of 2(2-ethyl)butylcyclohexanone (Aldrich, 10.1 g, 55.5 mmol)was converted to the title compound by the method of EXAMPLE 24 using5.4 g (77.7 mmol) of hydroxylamine hydrochloride and 8.2 g (99.9 mmol)of NaOAc in a mixture of 90 mL of EtOH and 90 mL of water. The procedureproduced 11.9 g (100%) of the crude title compound.

EXAMPLE 194 3-(2-ethylbutyl)hexahydro-1H-azepin-2-one, mixture with7-(2-ethylbutyl)hexahydro-1H-azepin-2-one

The product of EXAMPLE 193 (7.3 g, 37.1 mmol) was converted to the titlecompound mixture of two regioisomers by the method of EXAMPLE 29 using7.1 g (40.0 mmol) of benzene sulfonylchloride. The crude pale yellow oilproduct mixture (7.3 g) was separated into its Isomer-A and Isomer-Bcomponents by chromatography.

EXAMPLE 195 6-(2-ethylbutyl)-3,4,5, 6-tetrahydro-7-methoxy-2H-azepine

The Isomer-A product of EXAMPLE 194 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 196 2-(2-ethylbutyl)-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The Isomer-B product of EXAMPLE 194 (520 mg, 2.6 mmol) was reacted withtrimethyloxonium tetrafluoroborate (506 mg, 3.4 mmol) by the method ofEXAMPLE 26 to yield, after chromatography, 472 mg (85%) of the titlematerial.

EXAMPLE 197 3-(2-ethylbutyl)hexahydro-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 195 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 198 7-(2-ethylbutyl)hexahydro-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 196 (470 mg, 2.2 mmol) in 18 mL of MeOH wasreacted with ammonium chloride (98 mg, 1.8 mmol) by the method ofEXAMPLE 27 to yield 242 mg of the title material.

EXAMPLE 199 hexahydro-7-imino-1H-azepine-2-ethanol, monohydrochloride

Hexahydro-7-(2-propenyl)-1H-azepin-2-imine, monohydrochloride (theproduct of EXAMPLE 108) (3.0 g, 14.7 mmol) is dissolved in a mixture ofmethylene chloride (100 mL) and methanol (50 mL) and cooled to −78° C.Ozone is then bubbled through until a blue color is observed. Thereaction is flushed with N₂ to remove excess ozone. The reaction mixtureis warmed to room temperature and concentrated in vacuo to a residue.The residue is dissolved in ethanol (100 mL), cooled to 0° C., andvigorously stirred as a cold solution of sodium borohydride (0.7 g, 18.5mmol) in 1:1 ethanol-water is added. The pH of the reaction mixture ismaintained by the concomitant addition of 2 M acetic acid in water,maintaining the pH (pH paper) at 8 to 9. After the addition is complete,the mixture is stirred at room temperature for 10 hr, the reactionmixture is acidified to pH 2 with dilute HCl, and the reaction mixtureis concentrated in vacuo to a gum. The gum is dissolved in a smallamount of ethanol, filtered, evaporated in vacuo to a solid, dissolvedin water and applied to an ion exchange column of Dowex 50 (H⁺). Thecolumn is washed with deionized water, and the title compound elutedwith 2 N HCl. The eluate is concentrated in vacuo to a solid, dissolvedin a small amount of water, filtered, and lyophilized to give the titlecompound. C₈H₁₆N₂O.HCl mw=192.69

EXAMPLE 200 hexahydro-7-imino-1H-azepine-2-acetic acid,monohydrochloride

Hexahydro-7-(2-propenyl)-1H-azepin-2-imine, monohydrochloride (theproduct of EXAMPLE 108) (3.0 g, 14.7 mmol) is dissolved in methyl ethylketone (150 mL) and cooled to −78° C. Ozone is then bubbled throughuntil a blue color is observed. A 10% solution of H₂O₂ (12 mL) is addedat −78° C. The reaction mixture is allowed to warm to room temperatureand concentrated in vacuo to a solid. The solid is triturated withdiethyl ether, dried, dissolved in water, and lyophilized to give titlecompound. if purification is necessary, it is effected by dissolving thematerial in deionized water, and passing into a Dowex 50 ion exchangebed (H⁺). The resin is washed with deionized water, and the producteluted rapidly with 1 N ammonium hydroxide. The solution is rapidlyevaporated in vacuo at room temperature, and taken up in water. The pHis adjusted to 6.2 with 1 N HCl. The solution is concentrated in vacuoto a solid, the title compound. C₈H₁₄N₂O₂.HCl mw=206.67

EXAMPLE 201 methyl hexhydro-7-imino-1H-azepine-2-acetate,monohydrochloride

Thionyl chloride (3.5 g, 30 mmol) is added carefully and slowly to astirring volume of dry cold (−20° C.) methanol (150 mL). After additionis complete, the solution is stirred at −20° C. for 30 min. The titleproduct of EXAMPLE 200 (3.0 g, 14.6 mmol) is dissolved in the minimum ofdry methanol and treated with 3A molecular sieves. The mixture isfiltered protected from moisture, and added to the cold methanolic HClsolution. The reaction mixture is protected from moisture and allowed tostir at room temperature overnight. The reaction mixture is concentratedin vacuo to give the title product. C₉H₁₆N₂O₂.HCl mw=220.81

EXAMPLE 202 2-(2-propenyl)cycloheptanone, oxime

2-carboethoxycycloheptanone (1 mmol), finely powdered potassiumcarbonate (2 mmol), allyl bromide (1.5 mmol), and tetrabutyl ammoniumiodide (10 mg/mmol) are combined in dry DMF (1.25 mL/mmol) and stirredunder N₂ at 55 to 60° C. for 16 to 18 hours. The room temperaturereaction mixture is poured into water and extracted with Et₂O and EtOAc.The combined organics are washed with brine, dried, and stripped of allsolvent under reduced pressure to provide2-allyl-2-carboethoxycycloheptanone. This material is combined withlithium chloride (5 mmol), water (1.05 mmol) and dimethyl sulfoxide (5mL/mmol) and the mixture refluxed for approximately 4 hrs. The mixtureis poured into water and extracted with Et₂O and EtOAc. The combinedorganics are washed with brine, dried, and stripped of all solvent underreduced pressure to provide 2-allylcycloheptanone. A sample of the2-allylcycloheptanone is converted to the title compound by the methodof EXAMPLE 24 using hydroxylamine hydrochloride and NaOAc in a mixtureof EtOH and water.

EXAMPLE 203 octahydro-3-(2-propenyl)azocin-2-one, mixture withoctahydro-8-(2-propenyl)azocin-2-one

The product of EXAMPLE 202 is converted to the title compound mixture oftwo regioisomers by the method of EXAMPLE 29 using benzenesulfonylchloride. The crude product mixture is separated into itsIsomer-A and Isomer-B components by chromatography.

EXAMPLE 204 3,4,5,6,7,8-hexahydro-2-methoxy-3-(2-propenyl)azocine

The Isomer-A product of EXAMPLE 203 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 205 2,3,4,5,6,7-hexahydro-8-methoxy-2-(2-propenyl)azocine

The Isomer-B product of EXAMPLE 203 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 206 octahydro-3-(2-propenyl)azocin-2-imine, monohydrochloride

The product of EXAMPLE 204 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 207 octahydro-3-(2-propenyl)azocin-2-imine, monohydrochloride

The product of EXAMPLE 205 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 208 N-(2-butenyl)-2,2,2-trichloroacetamide

A solution of 3-butene-2-ol (8.7 mL, 100 mmol) in THF (50 mL) was addedto potassium hydride (KH, 600 mg, 15 mmol) over 15 min. The resultingalkoxide solution was added to a stirred solution oftrichloroacetonitrile (10.03 mL, 100 mmol) in ether (100 mL) at −10° C.The solution was stirred at 0° C. for 3 h, followed by removal ofsolvent under reduced pressure (temperature <25° C.); pentane (400 mL)and methanol (1 mL) were added, and the mixture filtered. Concentrationafforded a yellow oil (17.4 g). The oil was dissolved in xylene (450 mL)and refluxed for 2.5 h. The solvent was removed to yield 16.8 g of thetitle compound as a white solid.

EXAMPLE 209 3,3-dichloro-4-(1-chloroethyl)pyrrolidin-2-one

A mixture of the title compound in EXAMPLE 208 was treated withRUCl₂(PPh3)3 in refluxing xylene by the method of EXAMPLE 179 to producethe title material.

EXAMPLE 210 4-ethylpyrrolidin-2-one

A mixture of the title compound in EXAMPLE 209 was treated withtributyltin hydride and AIBN by the method of EXAMPLE 180 to produce thetitle material.

EXAMPLE 211 3-ethyl-3,4-dihydro-5-methoxy-2H-pyrrole

The product of EXAMPLE 180 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 212 4-ethylpyrrolidin-2-imine, monohydrochloride

The product of EXAMPLE 211 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 213 2,2,2-trichloro-N-(2-methylenebutyl)acetamide

Cis-2-pentene-1-ol was treated with NaH and trichloroacetonitrilefollowed by work up and treatment in refluxing xylene by the method ofEXAMPLE 208 to produce the material.

EXAMPLE 214 3,3-dichloro-4-(chloromethyl)-5-ethyl-pyrrolidin-2-one

A mixture of the title compound in EXAMPLE 213 was treated withRuCl₂(PPh₃)₃ in refluxing xylene by the method of EXAMPLE 179 to producethe title material.

EXAMPLE 215 5-ethyl-4-methylpyrrolidin-2-one

A mixture of the title compound in EXAMPLE 214 was treated withtributyltin hydride and AIBN by the method of EXAMPLE 180 to produce thetitle material.

EXAMPLE 216 2-ethyl-3, 4-dihydro-5-methoxy-3-methyl-2H-pyrrole

The product of EXAMPLE 215 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 217 5-ethyl-4-methylpyrrolidin-2-imine, monohydrochloride

The product of EXAMPLE 216 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 218 3,4-dihydro-5-methoxy-2S-(methoxymethyl)-2H-pyrrole

S-(+)-5-(hydroxymethyl)-2-pyrrolidinone is reacted with trimethyloxoniumtetrafluoroborate (2.2 equivelants) by the method of EXAMPLE 26 toproduce the title material.

EXAMPLE 219 5S-(methoxymethyl)pyrrolidin-2-imine, monohydrochloride

The product of EXAMPLE 218 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 220 3,4-dihydro-5-methoxy-2R-(methoxymethyl)-2H-pyrrole

R-(−)-5-(hydroxymethyl)-2-pyrrolidinone is reacted with trimethyloxoniumtetrafluoroborate (2.2 equivelants) by the method of EXAMPLE 26 toproduce the title material.

EXAMPLE 221 5R-(methoxymethyl)pyrrolidin-2-imine, monohydrochloride

The product of EXAMPLE 220 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 222 ethyl 3,4-dihydro-5-methoxy-2H-pyrrole-2S-carboxylate

Ethyl (S)-(+)-2-pyrrolidinone-5-carboxylate is reacted withtrimethyloxonium tetrafluoroborate by the method of EXAMPLE 26 toproduce the title material.

EXAMPLE 223 ethyl 5-iminopyrrolidine-2S-carboxylate, monohydrochloride

The product of EXAMPLE 222 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 224 5S-(bromomethyl)pyrrolidin-2-one

A solution of S-(+)-5-(hydroxymethyl)-2-pyrrolidinone (2 g, 17.4 mmol)in CH₂Cl₂ (160 mL) was treated with triphenylphosphine (10.5 g, 40 mmol)and carbontetrabromide (13.25 g, 40 mmol). The resulting solution wasstirred for 18 h followed by concentration and chromatography (40:1EtOAc/hexane, silica gel) to yield 1.32 g of the title compound as awhite solid.

EXAMPLE 2253-[[(5-oxopyrrolidin-2S-yl)methyl]oxy]-2S-[[(phenylmethoxy)carbonyl]amino]propanoicacid

A solution of N-α-Cbz-serine in DMF is treated with 2 equivalents of NaHat 0° C., followed by the addition of the title compound of EXAMPLE 224.The resulting solution is stirred for 5 h at RT, water is added and themixture extracted with EtOAc. The solution is acidified to pH 3.5 withcitric acid and extracted with EtOAc, dried and concentrated to yieldthe title compound.

EXAMPLE 226 methyl3-[[(5-oxopyrrolidin-2S-yl)methyl]oxy]-2S-[[(phenylmethoxy)carbonyl]amino]propanoate

The product of EXAMPLE 225 in DMF is treated with cesium carbonatefollowed by methyl iodide. The resulting mixture is filtered thenpartioned between EtOAc and water. The organic phase is washed withbrine, dried and concentrated to yield the title compound.

EXAMPLE 227 methyl3-[[(3,4-dihydro-5-methoxy-2H-pyrrolidin-2S-yl)methyl]oxy]-2S-[[(phenylmethoxy)carbonyl]amino]propanoate

The product of EXAMPLE 226 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 228 methyl3-[[(5-iminopyrrolidin-2S-yl)methyl]oxy]-2S-[[(phenylmethoxy)carbonyl]amino]propanoate,monohydrochloride

The product of EXAMPLE 227 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 229 methyl2S-amino-3-[[(5-iminopyrrolidin-2S-yl)methyl]oxy]propanoate,dihydrochloride

The product of EXAMPLE 228 in MeOH/HCl is reacted with H₂ over Pd/C 10%to generate the title material.

EXAMPLE 230 3-(7-iminoazepin-2-yl)-1,2-propanediol, monohydrochloride

To the product of EXAMPLE 108 in a mixture of acetone and THF is addedosmium tetroxide. An aqueous solution of morpholine N-oxide is thenadded to the reaction and the mixture is stirred at room temperatureover night. Sodium bisulfite is then added and this mixture isevaporated in vacuo to a solid. The solid is extracted with methanolthrice, and the combined extracts are evaporated in vacuo to a solid.This solid is dissolved in water and applied to a Dowex-50 ion exchangecolumn (H⁺), which is eluted with water and then 0.2 N HCl to yield thetitle compound.

EXAMPLE 231 6-[(tetrahydropyran-2-yl)oxy]hex-2-en-1-ol

The title compound was prepared from the mono THP ether of1,4-butanediol as reported in V. S. Martin, et. al., Tet. Lett. vol. 31,No. 5, pp 763-766 1990.

EXAMPLE 2322,2,2-trichloro-N-[1-ethenyl-4-[(tetrahydropyran-2-yl)oxy]butyl]acetamide

The product of EXAMPLE 231 is treated with NaH and trichloroacetonitrilefollowed by work up and treatment in refluxing xylene by the method ofEXAMPLE 208 to produce the material.

EXAMPLE 2333,3-dichloro-4-(chloromethyl)-5-[3-[(tetrahydropyran-2-yl)oxy]propyl]pyrrolidin-2-one

A mixture of the title compound in EXAMPLE 232 is treated withRuCl₂(PPh₃)₃ in refluxing xylene by the method of EXAMPLE 179 to producethe material.

EXAMPLE 2344-methyl-5-[3-[(tetrahydropyran-2-yl)oxy]propyl]pyrrolidin-2-one

A mixture of the title compound in EXAMPLE 233 is treated withtributyltin hydride and AIBN by the method of EXAMPLE 180 to produce thetitle product.

EXAMPLE 235 5-(3-hydroxypropyl)-4-methylpyrrolidin-2-one

A mixture of the title compound of EXAMPLE 234 is treated with aceticacid:THF:water (4:2:1), and concentrated. The resulting material ispurified by column chromatography to yield the title material.

EXAMPLE 236 5-(3-bromopropyl)-4-methylpyrrolidin-2-one

A mixture of the title compound of EXAMPLE 235 is treated withtriphenylphosphine and carbon tetrabromide by the method of EXAMPLE 224to generate the title material.

EXAMPLE 237 ethyl α-amino-3-methyl-5-oxopyrrolidine-2-pentanoate

A solution of N-(diphenylmethylene)glycine ethyl ester (Aldrich, 37mmol) in THF (20 mL) is added to −72° C. solution of sodium bis(trimethylsilylamide) (35 mmol, 0.5 M in THF), while the solution iskept below −65° C. The resulting solution is then stirred at −72° C. for30 min.; followed by the rapid addition of a cooled solution (−72° C.)of the product from EXAMPLE 236 (24 mmol) in THF via canula. The coolingbath is removed immediately and the mixture allowed to warm to 0° C. for4 h. The reaction mixture is partitioned between ether and 10% aqueoussodium bisulfate, then dried and concentrated. The product is purifiedby column chromatography. This intermediate is then treated with 0.1 Naqueous hydrochloric acid for 3 h, followed by extraction with ether andlyophilization of the aqueous solution, to yield the title material.

EXAMPLE 238 ethylα-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-5-oxopyrrolidine-2-pentanoate

A solution of compound in EXAMPLE 237 is treated withdi-t-butyldicarbonate in dichloromethane with triethylamine present. Thereaction mixture is extracted with water, dried (MgSO₄), filtered andstripped to afford the title compound.

EXAMPLE 239 ethyl α-[[(1,1-dimethylethoxy)carbonyl]amino]-3,4-dihydro-5-methoxy-3-methylpyrrolidine-2-pentanoate

The product of EXAMPLE 238 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 240 ethyl α-amino-5-imino-3-methylpyrrolidine-2-pentanoate,dihydrochloride

The product of EXAMPLE 239 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27. This material is then treated with 3MHCl/ethyl acetate to generate the title material.

EXAMPLE 241 hexahydro-7-[(oxiran-2-yl)methyl]-1H-azepin-2-one

The title product isomer B of EXAMPLE 104 (2.99 g, 19.5 mmol) in 150 mLof CH₂Cl₂ was refluxed with meta-chloroperbenzoic acid (MCPBA, 5.05 g,29.3 mmol) for 3 hr. After stirring at room temperature overnight, anadditional 1.0 g (5.8 mmol) of MCPBA was added and the reactionre-heated to reflux for an additional 6 hr. Solvent removal, followed bydissolution in EtOAc (150 mL) and washing 3×50 mL with saturated NaHCO₃provided crude desired product. Purification via flash columnchromatography using 100% EtOAc and deactivated silica gel yielded 2.25g (68%) of the title compound.

EXAMPLE 242 ethylα-[(diphenylmethylene)amino]hexahydro-7-oxo-1H-azepine-2-pentanoate

Under an argon atmosphere, the anion of title product isomer B ofEXAMPLE 241 (1.0 g, 5.91 mmol) is formed in tetrahydrofuran (THF, 30 mL)at −78° C. with lithium bis(trimethylsilyl)amide in THF (5.91 mmol). Thesolution in warmed to −60° C., then cooled back to −78° C. To this isadded the anion of N-(diphenylmethylene)glycine ethyl ester (formed byits reaction with lithium bis(trimethylsilyl)amide in THF (5.91 mmol) at−78° C. The solution is allowed to warm to room temperature overnight.Quenching with saturated NH₄Cl, followed by extraction into EtOAc (3×100mL) provides crude title material and its lactone derivative.Purification via flash column chromatography yields clean titlecompound.

EXAMPLE 243 ethylα-[(diphenylmethylene)amino]-3,4,5,6-tetrahydro-γ-dimethoxy-2H-azepine-2-pentanoate

The title product of EXAMPLE 242 is treated with trimethyloxoniumtetraflouroborate (two equivalents) in CH₂Cl₂ by the method of EXAMPLE26 to yield title material.

EXAMPLE 244 ethyl α-amino-7-imino-γ-methoxy-1H-azepine-2-pentanoate,dihydrochloride

The product of EXAMPLE 243 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27. This material is then lyophilized from aqueousHCl to generate the title material.

EXAMPLE 245 ethyl2-amino-5-(hexahydro-7-oxo-1H-azepin-2-yl)-3-pentenoate,monohydrochloride

The product of EXAMPLE 242 is stirred with aqueous HCl to yield thetitle product.

EXAMPLE 246 ethyl α-aminohexahydro-7-oxo-1H-azepine-2-pentanoate,monohydrochloride

The product of EXAMPLE 245 is reduced via hydrogenation using palladiumon carbon as catalyst to produce the title material.

EXAMPLE 247 ethylhexahydro-7-oxo-α-[[(phenylmethoxy)carbonyl]amino]-1H-azepine-2-pentanoate

The product of EXAMPLE 246 is treated with benzyl chloroformate understandard conditions to yield title product.

EXAMPLE 248 ethyl3,4,5,6-tetrahydro-7-methoxy-α-[[(phenylmethoxy)carbonyl]amino]-2H-azepine-2-pentanoate

The product of EXAMPLE 247 is treated with trimethyloxoniumtetraflouroborate in CH₂Cl₂ by the method of EXAMPLE 26 to yield titlematerial.

EXAMPLE 249 ethylhexahydro-7-imino-α-[[(phenylmethoxy)carbonyl]amino]-1H-azepine-2-pentanoate,monohydrochloride

The product of EXAMPLE 248 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 250 ethyl α-aminohexahydro-7-imino-1H-azepine-2-pentanoate,dihydrochloride

The product of EXAMPLE 249 is reduced using hydrogen and Pd/C ascatalyst to yield the title product after lyophilization from aqueousHCl.

EXAMPLE 251 2-(cyclohexen-1-yl)cyclohexanone, oxime

A sample of the 2-(1-cyclohexenyl)cyclohexanone (Lancaster) is convertedto the title compound by the method of EXAMPLE 24 using hydroxylaminehydrochloride and NaOAc in a mixture of EtOH and water.

EXAMPLE 252 7-(cyclohexen-1-yl)hexahydro-1H-azepin-2-one

The product of EXAMPLE 251 is converted to the title compound bystirring it with the reagent trimethylsilyl polyphosphate in benzene(preformed by refluxing a mixture of phosphorous pentoxide andhexamethyldisiloxane in benzene until the mixture becomes homogeneous inappearance) at room temperature overnight followed by an aqueous quenchand workup.

EXAMPLE 253 2-(cyclohexen-1-yl)-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The product of EXAMPLE 252 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 254 7-(cyclohexen-1-yl)hexahydro-1H-azepin-2-imine,monohydrochloride

The product of EXAMPLE 253 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 255 2-(2-butynyl)cyclohexanone, oxime

A sample of the 2-carboethoxycyclohexanone is reacted with1-bromo-2-butyne by the method of EXAMPLE 202 using potassium carbonatein DMF at 60° C. followed decarboethoxylation in refluxing mixture ofDMSO, lithium chloride, and water followed by conversion to its oximeusing a mixture of hydroxylamine hydrochloride, NaOAc, EtOH and water.

EXAMPLE 256 7-(2-butynyl)hexahydro-1H-azepin-2-one

The product of EXAMPLE 255 is converted to the title compound by themethod of EXAMPLE 29 using benzene sulfonylchloride.

EXAMPLE 257 2-(2-butynyl)-3,4,5,6-tetrahydro-7-methoxy-2H-azepine

The product of EXAMPLE 256 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 258 7-(2-butynyl)hexahydro-1H-azepin-2-imine, monohydrochloride

The product of EXAMPLE 257 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 259 1,1-dimethylethylN-[1-ethenyl-4-(3-methyl-5-oxopyrrolidin-2-yl)butyl]carbamate

To a stirring solution of the product of EXAMPLE 238 (20 mmol) in drytoluene cooled to −70° C. is added dropwise 1M DIBAL-H in toluene (40mL, 40 mmol). The solution is stirred for an additional 20 min and thereaction is quenched with MeOH. Upon removal of the ice bath, 150 mL ofsaturated solution of Rochelle salt is added to the reaction. Afterstirring for 1 h, the layers are separated. The aqueous layer isextracted with EtOAc. The combined organic layers are washed with H₂O,dried, filtered, and concentrated. The residue is purified bychromatography to yield the aldehyde which is directly used in the nextstep. To a stirring suspension of methyltriphenylphosphonium bromide(2.18 g, 6.1 mmol) in Et₂O is added dropwise 0.5 M potassiumhexamethyldisilazide in toluene (12.2 mL, 6.1 mmol). After stirring for1.5 h, the aldehyde from above (6.1 mmol) in Et₂O is added. After 16 h,a white solid is filtered from the reaction and the filtrate isconcentrated. The residue is purified by chromatography to yield thetitle compound.

EXAMPLE 260 1,1-dimethylethylN-[l-(1,2-dihydroxyethyl)-4-(3-methyl-5-oxopyrrolidin-2-yl)butyl]carbamate

To a stirring solution of the compound from EXAMPLE 259 (3.3 mmol) in 80mL of acetone:H₂O (3:1) is added N-methylmorpholine N-oxide (0.64 g, 4.8mmol) and 2.5% OsO₄ in t-BuOH (3.4 mL, 3.4 mmol). After 18 h, 120 mL ofH₂O, 8 g of celite, and 1.6 g Na₂S₂O₄ is added to the reaction. Thereaction is filtered through a pad of wet celite. To the filtrate isadded 200 mL of 1M KHSO₄. The filtrate is extracted with 3×200 mL EtOAc.The combined organic layers are dried, filtered, and stripped. Theresidue is purified by chromatography to yield the title compound.

EXAMPLE 261 1,1-dimethylethylN-[4-(3-methyl-2-oxopyrrolidin-2-yl)-1-(2-oxo-1,3-dioxolan-4-yl)butyl]carbamate

The product of EXAMPLE 260 in pyridine is treated with phosgene intoluene for 1 h, to produce the title material.

EXAMPLE 262 1,1-dimethylethylN-[4-(3,4-dihydro-5-methoxy-3-methyl-2H-pyrrol-2-yl)-1-(2-oxo-1,3-dioxolan-4-yl)butyl]carbamate

The product of EXAMPLE 261 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 2634-[1-amino-4-(5-imino-3-methylpyrrolidin-2-yl)butyl]-1,3-dioxolan-2-one,dihydrochloride

The product of EXAMPLE 262 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27, then teated with 3M HCl/EtOAc to generate thetitle material.

EXAMPLE 264 3-amino-6-(5-iminopyrrolidin-2-yl)-1,2-hexanediol

The product of EXAMPLE 263 is treated with aqueous barium hydroxide at70° C. to yield the title material.

EXAMPLE 265 4-methyl-5-(2-propenyl) pyrrolidin-2-one

The product of EXAMPLE 235 is treated with PTSA in refluxing toluene,with a Dean-Stark trap to remove water. The solvent is removed to yieldthe title material.

EXAMPLE 266 3,4-dihydro-5-methoxy-3-methyl-2-(2-propenyl)-2H-pyrrole

The product of EXAMPLE 265 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 267 4-methyl-5-(2-propenyl)pyrrolidin-2-imine, monohydrochloride

The product of EXAMPLE 266 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27 to generate the title material.

EXAMPLE 268 1,1-dimethylethylN-[4-(hexahydro-7-oxo-1H-azepin-2-yl)-1-(2-propenyl)butyl]carbamate

The product of EXAMPLE 246 is treated with di-t-butyldicarbonate by themethod of EXAMPLE 238. The resulting Boc-protected product is thenreacted with DIBAL and then methyltriphenyl-phosphonium bromide by themethod of EXAMPLE 260 to generate the title material.

EXAMPLE 269 1,1-dimethylethylN-[l-(1,2-dihydroxyethyl)-4-(hexahydro-7-oxo-1H-azepin-2-yl)butyl]carbamate

To the product of EXAMPLE 268 in a mixture of acetone and THF is addedosmium tetroxide. An aqueous solution of morpholine N-oxide is thenadded to the reaction and the mixture is stirred at room temperatureovernight. Sodium bisulfite is then added and this mixture afterdiluting with EtOAc is washed with brine, dried, filtered and strippedof all solvent under reduced pressure. The residue is purified bychromatography to yield the title compound.

EXAMPLE 270 1,1-dimethylethylN-[4-(hexahydro-7-oxo-1H-azepin-2-yl)-1-(2-oxo-1,3-dioxolan-4-yl)butyl]carbamate

The product of EXAMPLE 269 is reacted with phosgene by the method ofEXAMPLE 261, to generate the title material.

EXAMPLE 271 1,1-dimethylethylN-[l-(2-oxo-1,3-dioxolan-4-yl)-4-(3,4,5,6-tetrahydro-7-methoxy-2H-azepin-2-yl)butyl]carbamate

The product of EXAMPLE 270 is reacted with trimethyloxoniumtetrafluoroborate by the method of EXAMPLE 26 to produce the titlematerial.

EXAMPLE 2724-[1-amino-4-(hexahydro-7-imino-1H-azepin-2-yl)butyl]-1,3-dioxolan-2-one,dihydrochloride

The product of EXAMPLE 271 in MeOH is reacted with ammonium chloride bythe method of EXAMPLE 27. This product is then teated with 3M HCl/EtOActo generate the title material.

EXAMPLE 273 3-amino-6-(hexahydro-7-imino-1H-azepin-2-yl)-1,2-hexanediol

The product of EXAMPLE 272 is treated with aqueous barium hydroxide at70° C., to yield the title material.

EXAMPLE 274 2S-amino-3-[(5-iminopyrrolidin-2S-yl)methyl]oxy]propanoicacid, dihydrochloride

The product of EXAMPLE 229 in 2N HCl is refluxed for 1 h, followed bylyophilization to generate the title material.

EXAMPLE 275 hexahydro-7-(2-propenyl)-1H-azepin-2-one, oxime

Into a 50 mL roundbottom flask under an argon atmosphere was placedhydroxylamine hydrochloride (0.14 g, 2.02 mmol) and sodium methoxide(0.107 g, 1.99 mmol) in methanol (15 mL). To this was added the productof EXAMPLE 106 (0.29 g, 1.73 mmol). The reacyion was heated to refluxfor 12.5 h. The reaction was cooled to room temperature and all solventremoved in vacuo. The product was purified via reverse phasechromatography using a YMC ODS2 (20×25 mm) column and a mobile phase of30% acetonitrile/water.

¹H NMR (400 MHz, D₂O) δ5.9-5.8 (m, 1H), 5.3-5.15 (m, 2H), 3.8-3.7 (m,1H), 2.75-2.65 (m, 1H), 2.6-2.4 (m, 3H), 2.0-1.85 (m, 3H,), 1.75-1.6 (m,1H), 1.55-1.4 (m, 2H).

Elemental analysis: C₉H₁₆N₂O.1.3 HCl.1.1 H₂O (MW=235.46)

C H N Cl Calculated: 45.91 8.35 11.90 19.57 Found: 45.96 8.17 11.6519.67

EXAMPLE 276 hexahydro-2-(2-propenyl)-1H-azepin-2-one, oxime

Following the method of EXAMPLE 275, the title compound was preparedfrom the title product of EXAMPLE 105.

¹H NMR (300 MHz, D₂O) d 5.9-5.7 (m, 1H), 5.3-5.1 (m, 2H), 3.6-3.5 (m,2H), 2.85-2.75 (m, 1H), 2.65-2.55 (m_(,) 1H), 2.45-2.35 (m, 1H,),1.9-1.5 (m, 7H).

Elemental analysis: C₉H₁₆N₂O.1.05 HCl.0.5 H₂O (MW=217.33)

C H N Cl Calculated: 49.74 8.46 12.89 17.13 Found: 49.73 8.11 12.8217.30

EXAMPLE 277 3-hydroxy-2-imino-6-methylpiperidine acetate

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 3-hydroxy-6-methyl-2-nitropyridine to the title compoundexcept the reaction was run at 55° C. Product was obtained as a darksolid which was recrystallized from EtOH/EtOAc to give light ambercrystals. The analysis of the product was found to be consistent withthe proposed structure. m.p. 158-160° C. MH+=129; ¹H NMR (D₂O):δ4.40-4.30 (m, 1H); 3.60-3.40 (m, 1H); 2.00-1.40 (m, 4H); 1.72 (s, 3H);1.10 (d, J=7 Hz, 3H).

Elemental analysis: C₈H₁₆N₂O₃.(0.15 H₂O)

C H N Calculated: 50.33 8.61 14.67 Found: 50.33 8.54 14.66

EXAMPLE 278 3-ethoxy-2-imino-6-methylpiperidine hydrochloride

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 3-ethoxy-2-nitropyridine to the title compound except thereaction was run at 55° C. Product was obtained as a dark oil which waspurified by C-18-reverse phase chromatography, eluting with H₂O/CH₃CN.Fractions containing the product were lyophilized, redissolved in 1N HCland lyophilized to give the product as a light yellow oil. The analysisof the product was found to be consistent with the proposed structure.MH+=143; ¹H NMR (D₂O): δ4.35-4.20 (m, 1H); 3.8-3.5 (m, 2H); 3.30-3.10(m, 2H); 2.25-2.10 (m, 1H); 2.0-1.5 (m, 3H); 1.07 (t, J=7 Hz, 3H).

EXAMPLE 279 2-imino-decahydroisoquinoline acetate

2-amino-isoquinoline (1 g), palladium black (0.5 g) and ammonium formate(1 g) were suspended in methanol (150 ml) with stirring. The reactionmixture was stirred over the weekend at 40° C. and the catalyst wasremoved by filtration. The filtrate was taken down to dryness and theresidue was triturated with dried ether to give3,4-benzo-2-iminopiperidine formate as a solid. ES-MS MH+=147.

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 3,4-benzo-2-iminopiperidine to the title compound exceptplatinum oxide was used as the catalyst. The product was recrystallizedfrom EtOAc/EtOH to give a light tan solid. The analysis of the productwas found to be consistent with the proposed structure. MH+=153; ¹H NMR(D₂O): δ3.4-3.1 (m, 3H); 2.6-2.4 (m, 1H); 2.20-1.00 (m, 10H); 1.75 (s,3H).

EXAMPLE 280 2-amino-5,6,7,8-tetrahydroisoquinoline acetate

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-aminoisoquinoline to the title compound except platinumoxide was used as the catalyst. The product was triturated with EtOH togive a white solid. The analysis of the product was found to beconsistent with the proposed structure. 1H NMR (D₂O): δ7.35 (d, J=6 Hz,1H); 6.55 (d, J=6 Hz, 1H); 2.6-2.5 (m, 2H); 2.20-2.10 (m, 2H); 1.75 (s,3H); 1.70-1.50 (m, 4H).

Elemental analysis: C₁₁H₁₆N₂O₂

C H N Calculated: 63.44 7.74 13.45 Found: 63.22 7.89 13.47

EXAMPLE 281 5-amino-2-iminopiperidine hydrochloride

2,5-diaminopyridine dihydrochloride (1.2 g) and platinum oxide (500 mg)in ethanol (20 mL) and conc HCl (2 mL) were shaken on a Parrhydrogenation apparatus at 55 psi of hydrogen overnight. Product wasobtained as a dark solid which was purified by C-18-reverse phasechromatography, eluting with H₂O/CH₃CN. Fractions containing the productwere lyophilized, redissolved in 1N HCl and lyophilized to give theproduct as a yellow solid. The analysis of the product was found to beconsistent with the proposed structure. MH+=114; ¹H NMR (D₂O): δ3.8-3.6(m, 2H); 3.4-3.25 (m, 1H); 2.75-2.65 (m, 2H); 2.25-2.15 (m, 1H);2.15-1.85 (m, 1H).

Elemental analysis: C₅H₁₃C₁₂N₃

C H N Calculated: 32.27 7.04 22.58 Found: 32.43 7.00 22.48

EXAMPLE 282 2-imino-4-piperidine carboxylic acid hydrochloride

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-aminopyridine-4-carboxylic acid to the title compoundexcept platinum oxide was used as the catalyst. Product dissolved in 3NHCl and lyophilized to give white solid, which was recrystallized fromEtOH to give product as a white solid. The analysis of the product wasfound to be consistent with the proposed structure. m.p. 230-234° C. ¹HNMR (D₂O): δ3.40-3.20 (m, 2H); 3.0-2.8 (m, 2H); 2.80-2.70 (m, 2H);2.20-2.00 (m, 1H); 2.00-1.80 (m, 1H).

Elemental analysis: C₆H₁₁ClN₂O₂

C H N Calculated: 40.35 6.21 15.68 Found: 40.43 6.20 15.29

EXAMPLE 283 5-amino-2-imino-4-methylpiperidine dihydrochloride (cis andtrans isomers)

The method of preparation of 5-amino-2-iminopiperidine hydrochloride wasused to convert 2-amino-4-methyl-5-nitropyridine to the title compound.Product was obtained as a white solid, shown to be two isomers by ¹H NMRanalysis. Recrystallization from EtOH/H₂O gave a white solid, shown tobe one isomer (A) by ¹H NMR and tentatively assigned the transconfiguration. The mother liquor was concentrated in vacuo andredissolved in warm EtOH. Upon cooling, the first crop was obtainedwhich contains more (A). The second crop contains a mixture of (A) and(B). The third crop is pure (B), which was tentatively assigned the cisconfiguration. The analysis of the product was found to be consistentwith the proposed structure. ¹H NMR (D₂O) of (A): δ3.8-3.7 (m, 1H);3.68-3.58 (m 1H); 3.50-3.40 (m, 1H); 2.90-2.75 (m, 1H); 2.45-2.35 (m,2H); 1.00 (d, J=7 Hz, 3H). ¹H NMR (D₂O ) of (B): δ3.75-3.65 (m, 1H);3.45-3.25 (m, 2H); 2.85-2.70 (m, 1H); 2.50-2.35 (m, 1H); 2.20-2.15 (m,1H); 1.05 (d, J=7 Hz, 3H).

Elemental analysis of (A) C₆H₁₅C₁₂N₃. (H₂O)

C H N Calculated: 33.04 7.86 19.26 Found: 33.01 7.39 19.20

Elemental analysis of (B): C₆H₁₅C₁₂N₃.(0.4 H₂O)

C H N Calculated: 34.76 7.68 20.27 Found: 34.53 7.54 20.67

EXAMPLE 284 Ethyl (2′-imino)-2-(3′-piperidineoxy)acetate hydrochloride

3-hydroxy-2-nitropyridine (5 g) and anhydrous potassium carbonate (5 g)were mixed in anhydrous DMF (75 mL) for 15 minutes. Ethyl bromoacetatewas added and contents were stirred overnight. The contents were pouredinto ice water and extracted with EtOAc (2×200 mL). The EtOAc extractswere combined, dried (MgSO₄) and concentrated in vacuo to give2′-nitro-2-(3′-pyridineoxy)acetate as a light yellow solid (6.6 g).

The method of preparation of 5-amino-2-iminopiperidine hydrochloride wasused to convert 2′-nitro-2-(3′-pyridineoxy)acetate to the titlecompound. Purification by C-18-reverse phase chromatography andrecrystallization from EtOH/EtOAc gave the product as a white solid. Theanalysis of the product was found to be consistent with the proposedstructure. MH+=201;

Elemental analysis: C₉H₁₇ClN₂O₃.(0.25 H₂O)

C H N Calculated: 44.82 7.31 11.61 Found: 44.92 7.62 11.75

EXAMPLE 285 2-imino-5-(n-butyl)piperidine acetate

Fusaric acid (2 g), diphenylphosphoryl azide (2.4 mL) and triethylamine(1.6 mL) in t-butanol (70 mL) were refluxed overnight. The contents wereconcentrated in vacuo and treated with 25% aqueous HBr (20 mL) for 24hours. After neutralizing with 50% NaOH, contents were extracted withCH₂Cl₂, dried (MgSO₄) and concentrated in vacuo to give2-amino-5-(n-butyl)pyridine as an oil (1.1 g).

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-5-(n-butyl)pyridine to the title compound exceptplatinum oxide was used as the catalyst. Product was triturated withether to give a white solid. The analysis of the product was found to beconsistent with the proposed structure. MH+=155; ¹H NMR (D₂O):δ3.35-3.25 (m, 1H); 2.85-2.75 (m, 1H); 2.60-2.35 (m, 2H); 1.85-1.55 (m,2H); 1.75 (s, 3H); 1.35-1.05 (m, 7H); 0.75-0.65 (m, 3H).

EXAMPLE 286 2-imino-5-(trifluoromethyl)piperidine hydrochloride

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-3-chloro-5-(trifluoromethyl)pyridine to the titlecompound except platinum oxide was used as the catalyst. Product wastriterated with ether to give a white solid. The analysis of the productwas found to be consistent with the proposed structure. MH+=167; ¹H NMR(D₂O): δ3.65-3.50 (m, 1H); 3.40-3.20 (m, 1H); 2.85-2.45 (m, 3H);2.15-2.00 (m, 1H); 1.80-1.60 (m, 1H).

Elemental analysis: C₆H₁₀ClF₃N₂.(0.1 H₂O)

C H N Calculated: 35.26 5.03 13.70 Found: 34.91 4.97 13.64

EXAMPLE 287 O-[3-(2-iminopiperidinyl)]-4-amino-1-butanol

3-hydroxy-2-nitropyridine (5 g) and anhydrous potassium carbonate (5 g)were mixed in anhydrous DMF (75 mL) for 15 minutes.4-Bromo-butyronitrile (3.6 mL) was added and contents were stirredovernight. Contents were poured into ice water and4-[2′-nitro-(3′-pyridineoxy)]butyronitrile, as a white solid, wasfiltered.

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 4-[2′-nitro-(3′-pyridineoxy)]butyronitrile to the titlecompound except platinum oxide was used as the catalyst. Purification byC-18 reverse phase chromatography and crystallization from EtOAc/EtOHgave the product as a white solid. The analysis of the product was foundto be consistent with the proposed structure. MH+=185; ¹H NMR (D₂O):δ3.75-3.65 (m, 1H); 3.50-3.40 (m, 2H); 3.30-2.85 (m, 6H); 1.80-1.45 (m,8H).

Elemental analysis: C₉H₂₁Cl₂N₃O

C H N Calculated: 41.87 8.20 16.28 Found: 41.83 8.33 15.98

EXAMPLE 288 4-amino-2-iminopiperidine dihydrobromide

4-Amino-3,5,6-trichloropicolinic acid (1.0 g), diphenylphosphorylazide(1.0 mL) and triethylamine (0.6 mL) in t-butanol (35 mL) were refluxedovernight. Contents were concentrated in vacuo leaving a white solid,which was treated with 25% aqueous HBr (20 mL) for 24 hours.2,4-diamino-3,5,6-trichloropyridine dihydrobromide was filtered as alight yellow solid (1.2 g).

2,4-Diamino-3,5,6-trichloropyridine dihydrobromide (1.1 g) and platinumoxide (520 mg) in ethanol (50 mL) were shaken on a Parr hydrogenationapparatus at 55 psi of hydrogen for 48 hours. The contents were filteredand the filtrate was concentrated in vacuo leaving a waxy solid. Thesolid was triturated with ether/EtOH to give 4-amino-2-iminopiperidinedihydrobromide as a white solid. The analysis of the product was foundto be consistent with the proposed structure. MH+=114; ¹H NMR (D₂O):δ3.80-3.60 (m, 1H); 3.55-3.25 (m, 1H); 3.08-2.95 (m, 1H); 2.76-2.62 (m,1H); 2.25-2.13 (m, 1H); 1.95-1.80 (m, 1H).

EXAMPLE 289 5-aminomethyl-2-imino-4,6-dimethylpiperidine dihydrochloride

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-5-cyano-4,6-dimethylpyridine to the title compoundexcept platinum oxide was used as the catalyst. Product was treated withEtOH to give a white solid. The analysis of the product was found to beconsistent with the proposed structure. MH+=156; ¹H NMR (D₂O):δ3.63-3.40 (m, 2H); 3.20-3.05 (m, 1H); 2.70-2.58 (m, 1H); 2.40-2.20 (m,1H); 2.05-1.80 (m, 2H); 1.22 (d, J=7 Hz, 3H); 0.95 (d,J=7 Hz, 3H).

EXAMPLE 290 2-imino-6-methyl-4-(trifluoromethyl)piperidine hydrochloride

2-chloro-6-methyl-4-(trifluoromethyl)pyridine (5.0 g) and conc ammoniumhydroxide (150 mL) were heated at 180° C. in a steel reaction vesselwith mechanical stirring overnight. The contents were allowed to cooland partitioned between CH₂Cl₂ and water. The CH₂Cl₂ layer was dried(MgSO₄) and concentrated in vacuo leaving2-amino-6-methyl-4-(trifluoromethyl)pyridine as a white solid.

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-6-methyl-4-(trifluoromethyl)pyridine to the titlecompound. Product was triturated with EtOAc/EtOH to give a white solid.The analysis of the product was found to be consistent with the proposedstructure. MH+=181; ¹H NMR (D₂O): δ3.60-3.40 (m, 1H); 2.80-2.50 (m, 3H);2.20-2.05 (m, 1H); 1.42-1.25 (m, 1H); 1.15 (d, J=7 Hz, 3H).

Elemental analysis: C₇H₁₂ClF3N₂.(0.25 H₂O)

C H N Calculated: 38.02 5.70 12.67 Found: 37.98 5.54 12.84

EXAMPLE 291 2-imino-4-(trifluoromethyl)piperidine hydrochloride

The method of preparation of2-amino-6-methyl-4-(trifluoromethyl)pyridine was used to convert2-chloro-4-(trifluoromethyl)pyridine to2-amino-4-(trifluoromethyl)pyridine.

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-4-(trifluoromethyl)pyridine to the title compound.The product was triturated with EtOAc to give a white solid. Theanalysis of the product was found to be consistent with the proposedstructure. MH+=167; ¹H NMR (D₂O): δ3.45-3.35 (m, 1H); 3.30-3.20 (m, 1H);2.85-2.55 (m, 3H); 2.10-2.00 (m, 1H); 1.80-1.60 (m, 1H).

Elemental analysis: C₆H₁₀ClF3N₂

C H N Calculated: 35.57 4.98 13.83 Found: 35.17 4.76 13.70

EXAMPLE 292 2-imino-3-(trifluoromethyl)piperidine trifluoroacetate

The method of preparation of2-amino-6-methyl-4-(trifluoromethyl)pyridine was used to convert2-chloro-3-(trifluoromethyl)pyridine to2-amino-3-(trifluoromethyl)pyridine.

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-3-(trifluoromethyl)pyridine to the title compound.Product was crystallized from EtOAc/hexanes to give a white solid. Theanalysis of the product was found to be consistent with the proposedstructure. MH+=167; ¹H NMR (D₂O): δ3.70-3.50 (m, 1H); 3.35-3.20 (m, 2H);2.10-1.60 (m, 4H).

Elemental analysis: C₈H₁₀F₆N₂O₂

C H N Calculated: 34.30 3.60 10.00 Found: 34.55 3.65 10.01

EXAMPLE 293 2-imino-6-(trifluoromethyl)piperidine acetate

The method of preparation of2-amino-6-methyl-4-(trifluoromethyl)pyridine was used to convert2-chloro-6-(trifluoromethyl)pyridine to2-amino-6-(trifluoromethyl)pyridine.

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-6-(trifluoromethyl)pyridine to the title compound.Product was crystallized from EtOAc to give a white solid. The analysisof the product was found to be consistent with the proposed structure.MH+=167; ¹H NMR (D₂O): δ4.20-4.00 (m, 1H); 2.60-2.50 (m, 2H); 2.05-1.50(m, 4H); 1.80 (s, 3H).

EXAMPLE 294 2-imino-4-(n-propyl)piperidine acetate

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-4-(n-propyl)pyridine to the title compound exceptplatinum oxide was used as the catalyst. Product was triturated withEtOAc to give a white solid. The analysis of the product was found to beconsistent with the proposed structure. MH+141; ¹H NMR (D₂O):δ63.35-3.05 (m, 2H); 2.60-2.40 (m, 1H); 2.15-2.00 (m, 1H); 1.80-1.60 (m,2H); 1.78 (s, 3H); 1.35-1.05 (m, 5H); 0.75-0.65 (m, 3H).

EXAMPLE 295 2-imino-4-(n-ethyl)piperidine acetate

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-4-(n-ethyl)pyridine to the title compound exceptplatinum oxide was used as the catalyst. The product was crystallizedfrom cold EtOAc to give a white solid. The analysis of the product wasfound to be consistent with the proposed structure. MH+=127; ¹H NMR(D₂O): δ3.40-325 (m, 1H); 3.22-3.10 (m, 1H); 2.60-2.50 (m, 1H);2.15-2.00 (m, 1H); 1.85-1.75 (m, 1H); 1.78 (s, 3H); 1.70-1.60 (m, 1H);1.35-1.15 (m, 3H); 0.75 (t, J=7 Hz, 3H)

EXAMPLE 296 2-Iminododecamethylenimine Hydrochloride salt

To a solution of 1 g (0.0067 mol) of trimethyloxonium tetrafluoroboratein 10 mL of anhydrous chloroform was added 1.33 g (0.0067 mol) of2-azacyclotridecanone. This mixture was stirred at reflux for fourhours, then for 18 hours at 25° C. This mixture was then diluted withethyl acetate, washed with dilute potassium carbonate, dried (MgSO₄),filtered and concentrated to afford 1.3 g of a pink oil. This oil wasdissolved in 25 mL of methanol and 0.33 g (0.006 mol) of ammoniumchloride was added. After stirring at 25° C. for 72 hours, the mixturewas concentrated to afford 0.6 g of a white solid. It was extracted withwater, filtered and the filter was lyophilized to afford2-iminododecamethylenimine hydrochloride salt as a white fluffy solid.

¹H-NMR(D₂O) 1.1-1.3 (m, 14H), 1.45-1.65 (m, 4H), 2.35 (m, 2H), 3.2 (m,2H); Mass Spectra, M+H=197; Elemental analysis Calcd. forC₁₂H₂₅N₂Cl₁+2/3 N₁H₄Cl₁: C, 53.65; H, 10.39; N,13.92. Found C, 53.42; H,10.32; N, 13.58.

EXAMPLE 297 2-Imino-6-Cyclopentylpiperidine Trifluoroacetic acid salt

To a solution of 1 g (0.0067 mol) of trimethyloxonium tetrafluoroboratein 20 mL of anhydrous chloroform was added 0.5 g (0.003 mol) of6-cyclopentylvalerolactam. This mixture was stirred at reflux for threehours. This mixture was allowed to cool to 25° C., washed with dilutesodium bicarbonate, dried (MgSO₄), filtered and concentrated to afford ayellow oil. This oil was dissolved in 25 mL of methanol and 0.16 g ofammonium chloride was added. After stirring at 25° C. for 18 hours, themixture was concentrated to afford a white semisolid. Chromatography(C-18) afforded the pure 2-imino-6-cyclopentylpiperidine trifluoroaceticacid salt as a white solid. ¹H-NMR(D₂O) 1.05-1.2 (m, 2H), 1.35-1.95 (m,11H), 2.3-2.55 (m, 2H), 3.15-3.25 (m, 1H); Mass Spectra, M+H=167.

EXAMPLE 298 (2-Ethylimino)-4-methylpiperidine acetate

Hydrobromic acid (48%, 39.5 mL) was cooled to 0° C. and2-amino-4-picoline (Aldrich, 8.6 g, 0.08 mole) was added in portions. At0° C., bromine (12 mL, 0.234 mole) was added slowly dropwise, followedby dropwise addition of a solution of sodium nitrite (14.0 g) in water(20 mL) at 0° C. The contents were stirred 1½ hours at 0° C. beforeadding 50% aqueous sodium hydroxide (60 g), keeping the temperature lessthan 20° C. during the addition. Contents were stirred 1 hour andextracted with ether (2×200 mL). The ether layers were combined anddried over potassium hydroxide pellets for 1 hour, filtered andconcentrated in vacuo leaving an orange oil (12.4 g). The oil wasdistilled on a kugelrohr apparatus at 40° C. (0.25 mm) to give2-bromo-4-methylpyridine as a yellow oil (10.3 g).

2-Bromo-4-methylpyridine (1.5 g, 0.02 mole) and aqueous ethylamine (70%,100 mL) were heated at 150° C. overnight in a steel pressure reactor.Contents were allowed to cool and concentrated in vacuo. The residue wastriturated with CH₂Cl₂ and a white solid was filtered and discarded. Thefiltrate was concentrated in vacuo leaving an oil (950 mg). The oil wasdistilled on a kugelrohr apparatus at 90° C. (0.35 mm) to give2-(ethylamino)-4-methylpyridine as a white solid (670 mg).

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-(ethylamino)-4-methylpyridine to the title compound exceptplatinum oxide was used as the catalyst. The analysis of the product,obtained as an oil, was found to be consistent with the proposedstructure. MH+=141; ¹H NMR (D₂O): 3.40-3.10 (m, 2H); 3.00 (q, J=6 Hz,2H); 2.50-2.40 (m, 1H); 2.10-1.90 (m, 1H); 1.83 (s, 3H); 1.80-1.65 (m,4H); 1.40-1.20 (m 1H); 1.02 (t, J=6 Hz, 3H); 0.83 (d, J=6 Hz, 3H).

EXAMPLE 299 2-(N,N-dimethylamino)-4-methyl-3,4,5, 6-tetrahydropyridinehydrochloride

The method of preparation of 2-(ethylamino)-4-methylpyridine was used toconvert 2-bromo-4-methylpyridine to 2-(N,N-dimethylamino)-4-methylpyridine.

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-(N, N-dimethylamino)-4-methylpyridine to the title compoundexcept platinum oxide was used as the catalyst. The product was obtainedas a clear colorless oil which was dissolved in 3N HCl and lyophilizedto give the desired product as a waxy colorless solid. The analysis ofthe product was found to be consistent with the proposed structure.MH+=141; ¹H NMR (D₂O): 3.44-3.32 (m, 1H); 3.28-3.16 (m, 1H); 3.00 (s,3H); 2.90 (s, 3H); 2.76-2.64 (m, 1H); 2.08-1.94 (m, 1H); 1.88-1.68 (m,2H); 1.35-1.18 (m, 1H); 0.52 (d, J=6 Hz, 3H).

EXAMPLE 300 2′-(2-aminoethylimino)-5′-(trifluoromethyl)piperidinedihydrochloride

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2′-(2-aminoethylamino)-3′-chloro-5′-(trifluoromethyl)pyridineto the title compound. The analysis of the product, obtained as an oil,was found to be consistent with the proposed structure. MH+=210; ¹H NMR(D2O): 3.70-3.35 (m, 4H); 3.18 (t, J=6 Hz, 2H); 2.95-2.60 (m, 3H);2.20-2.00 (m, 1H); 1.90-1.70 (m, 1H).

EXAMPLE 301 6-Benzyl-2-iminopiperidine hydrochloride

2-benzylpyridine (Aldrich, 2.5 g, 0.015 mole), sodium amide (780 mg,0.02 mole) and N, N-dimethylaniline (25 mL) were refluxed overnight. Thecontents were allowed to cool and were partitioned between ether andwater. The ether layer was dried (MgSO4) and concentrated in vacuoleaving an oil. The oil was purified by chromatography. The purifiedmaterial was dissolved in 1N HCl, lyophilized, and triturated with EtOActo give 2-amino-6-benzylpyridine as a white solid.

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-6-benzylpyridine to the title compound. The productwas obtained as an oil which was purified by C-18 reverse phasechromatography to give a white solid. The solid was dissolved in 1 NHCl, lyophilized, and recrystallized from EtOH/EtOAc to give the desiredproduct as a white solid. The analysis of the product was found to beconsistent with the proposed structure. MH+=189; ¹H NMR (CDCl₃): 9.85(s, 1H); 8.95 (s, 1H); 8.62 (s, 1H); 7.40-7.10 (m, 5H); 3.80-3.60 (m,1H); 3.20-3.00 (m, 1H); 2.90-2.70 (m, 2H); 2.65-2.45 (m, 1H); 2.42-2.25(m, 2H); 1.92 (m, 2H); 1.75 (m, 1H); 1.50-1.35 (m, 1H).

EXAMPLE 302 2-(cyclohexylmethyl)-6-iminopiperidine hydrochloride

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-6-benzylpyridine to the title compound exceptplatinum oxide was used as the catalyst. The product was obtained as anoil which was dissolved in 1 N HCl and lyophilized to give a whitesolid. The solid was recrystallized from EtOAc to give the desiredproduct as white crystals. The analysis of the product was found to beconsistent with the proposed structure. MH+=195; ¹H NMR (CDCl₃): 9.60(s, 1H); 8.90 (s, 1H); 8.70 (s, 1H); 3.60-3.40 (m, 1H); 2.90-2.70 (m,1H); 2.70-2.50 (m, 1H); 2.10-1.80 (m, 2H); 1.80-1.00 (m, 13H); 1.00-0.80(m, 2H).

EXAMPLE 303 2-cyclohexyl-6-iminopiperidine hydrochloride

The method of preparation of 2-amino-6-benzylpyridine was used toconvert 2-phenylpyridine (Aldrich) to 2-amino-6-phenylpyridine.

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-amino-6-phenylpyridine to the title compound except thereaction was run at 55° C. The product was obtained as an oil which wascrystallized from EtOH/EtOAc to give the desired product as a whitesolid.

MH+181; ¹H NMR (CDCl₃): 3.30-3.15 (m, 1H); 2.50-2.30 (m, 2H); 1.85-1.68(m, 2H); 1.65-1.20 (m, 8H); 1.20-0.80 (m, 5H).

EXAMPLE 304 4-Methylpiperidine-2-hydrazone acetate

The method of preparation of 2-imino-4-methylpiperidine acetate was usedto convert 2-hydrazinopyridine (Aldrich) to the title compound exceptthe reaction was run in glacial acetic acid/water (2:1) for solubilityand platinum oxide was used for the catalyst. The product was obtainedas a clear colorless oil which crystallized under EtOAc and wasrecrystallized from ethanol. to give the desired as white crystals. Theanalysis of the product was found to be consistent with the proposedstructure. MH+=114; ¹H NMR (D₂O): 3.15-3.10 (m, 2H); 2.60-2.50 (m, 2H);1.98 (s, 3H); 1.80-1.60 (m, 4H).

EXAMPLE 305 4-Methyl-2-(propylimino)piperidine hydrochloride

The method of preparation of 2-(ethylimino)-4-methylpiperidine acetatewas used to convert 4-methyl-2-(propylamino)pyridine hydrochloride tothe title compound. The product was obtained as a clear colorless oilwhich crystallized under EtOAc. The analysis of the product was found tobe consistent with the proposed structure. MH+=155; ¹H NMR (D₂O):3.45-3.20 (m, 2H); 3.05 (t, J=6 Hz, 2H); 2.60-2.45 (m, 1H); 2.20-2.00(m,; 1.95-1.70 (m, 2H); 1.60-1.40 (m, 2H); 1.40-1.25 (m, 1H); 0.90 (d,J=6 Hz, 3H); 0.80 (t, J=6 Hz, 3H).

EXAMPLE 306 2-Iminohexamethylenimine Hydroiodide salt J. Med. Chem.21(10), 1044-54 (1978)

To a solution of 5 g (0.039 mol) of thiocaprolactam in 100 mL of acetonewas added 6.4 g (0.045 mol) of iodomethane. This mixture was stirred twodays at 25° C. Filtration afforded 9.5 g of the thio-iminoetherhydroiodide salt as a white solid, mp 177-181° C. Three grams of thisiminoether was dissolved in 80 mL of ethanol saturated with anhydrousammonia. This mixture was sealed and stirred at 25° C. for three days.Concentration to a reduced volume followed by ether trituration afforded2.2 g of the title product as a white solid, mp 135-141° C. ¹H-NMR(D₂O)1.45-1.55 (m, 2H), 1.55-1.7 (m, 4H), 2.5 (m, 2H), 3.28 (m, 2H); MassSpectra, M+H=113; Elemental analysis Calcd. for C₆H₁₃N₂I₁: C, 30.02; H,5.46; N,11.67. Found C, 29.99; H, 5.49; N, 11.61.

EXAMPLE 307 2-(Methylimino)hexamethylenimine Hydroiodide salt

To a solution of 1 g (0.0037 mol) of the thio-iminoether from EXAMPLE306 was added 40 mL of ethanol saturated with anhydrous methylamine.This mixture was sealed and stirred at 25° C. for three days.Concentration to a reduced volume followed by ether trituration afforded0.9 g of the title product as a white solid, mp 169-171° C. ¹H-NMR(D₂O)1.45-1.65 (m, 6H), 2.48 (m, 2H), 2.68 (s, 3H), 3.3 (m, 2H); MassSpectra, M+H=127; Elemental analysis Calcd. for C₇H₁₅N₂I₁: C, 33.09; H,5.95; N,11.02. Found C, 33.31; H, 5.94; N, 10.97.

EXAMPLE 308 1-Methyl-2-iminopentamethylenimine Hydroiodide salt

To a solution of 2 g (0.0155 mol) of N-methylthiovalerolactam in 40 mLof acetone was added 2.4 g (0.017 mol) of iodomethane. This mixture wasstirred three days at 25° C. Filtration and trituration with etherafforded 4 g of the thio-iminoether hydroiodide salt as a white solid,mp 153-155° C. One gram of this iminoether was dissolved in 50 mL ofethanol saturated with anhydrous ammonia. This mixture was sealed andstirred at 25° C. for eighteen hours. Concentration to a reduced volumefollowed by ether trituration afforded 0.8 g of the title product as awhite solid, mp 157-158° C. 1H-NMR(D2O) 1.6-1.7 (m, 2H), 1.7-1.8 (m,2H), 2.5 (t, 2H), 2.95 (s, 3H), 3.38 (t, 2H); Mass Spectra, M+H=113;Elemental analysis Calcd. for C₆H₁₃N₂I₁: C, 30.02; H, 5.46; N,11.67.Found C, 30.16; H, 5.49; N, 11.63.

EXAMPLE 309 1-Methyl-2-iminohexamethylenimine Hydroiodide salt

To a solution of 2 g (0.014 mol) of N-methylthiocaprolactam in 40 mL ofacetone was added 2.18 g (0.0154 mol) of iodomethane. This mixture wasstirred three days at 25° C. Filtration and trituration with etherafforded 3.8 g of the thio-iminoether hydroiodide salt as a white solid,mp 138-142° C. One gram of this iminoether was dissolved in 50 mL ofethanol saturated with anhydrous ammonia. This mixture was sealed andstirred at 25° C. for eighteen hours. Concentration to a reduced volumefollowed by ether trituration afforded 0.8 g of the title product as awhite solid, mp 137-139° C. ¹H-NMR(D₂O) 1.55-1.7 (m, 6H), 2.58 (m, 2H),3.02 (s, 3H), 3.55 (m, 2H); Mass Spectra, M+H=127; Elemental analysisCalcd. for C7H15N2I₁: C, 33.09; H, 5.95; N,11.02. Found C, 33.12; H,6.01; N, 11.07.

EXAMPLE 310 2-(Trifluoroethylimino)pentamethylenimine Hydroiodide salt

A mixture of 100 g (0.23 mol) of P₄S₁₀ and 24 g (0.23 mol) of Na₂CO₃ in1.5 L of anhydrous THF was stirred vigorously with a mechanical stirrerfor thirty minutes. To this stirred mixture was added 19 g (0.19 mol) ofvalerolactam. After stirring for three hours, the solution was dilutedwith 1 L of 10% aqueous Na₃PO₄, 750 mL of ethyl acetate and 750 mL ofhexanes. Organic layer was separated and the aqueous layer was extractedwith 500 mL of ethyl acetate. The organic extracts were combined, dried(MgSO₄), filtered through silica gel and concentrated to afford a whitesemi-solid. Trituration with hexanes-ether afforded 9.7 g ofthiovalerolactam as a white solid, mp 85-88° C. To a solution of 9 g(0.078 mol) of thiovalerolactam in 100 mL of acetone was added 11.8 g(0.083 mol) of iodomethane. This mixture was stirred for eighteen hoursat 25° C. Filtration and ether trituration afforded 18.5 g of thethio-iminoether hydroiodide salt as a white solid. To a solution of 0.2g (0.00077 mol) of the thio-iminoether in 3 mL of ethanol was added 0.2g (0.002 mol) of trifluoroethylamine. This mixture was sealed andstirred at 25° C. for eighteen hours. Evaporation of the solventafforded the title product as a white solid. ¹H-NMR(D₂O) 1.65-1.7 (m,4H), 2.58 (m, 2H), 3.32 (m, 2H), 3.95 (q, 2H); Mass Spectra, M+H=181.

EXAMPLE 311 2-(Cyclohexylimino)pentamethylenimine Hydroiodide salt

To a solution of 0.2 g (0.00077 mol) of the thio-iminoether from exampleRKW-E in 3 mL of ethanol was added 0.08 g (0.0008 mol) ofcyclohexylamine. This mixture was sealed and stirred at 25° C. foreighteen hours. Evaporation of the solvent afforded the title product asa white solid.

¹H-NMR(D₂O) 1.1-1.3 (m, 6H), 1.45-1.9 (m, 10H), 2.42 (t, 2H), 3.25 (t,3H), 3.95 (q, 2H); Mass Spectra, M+H=181.

EXAMPLE 312 2-(Dimethylaminopropylimino)pentamethylenimine Hydroiodidesalt

To a solution of 0.2 g (0.00077 mol) of the thio-iminoether from exampleRKW-E in 3 mL of ethanol was added 0.08 g (0.0008 mol) ofN,N-dimethylaminopropylamine. This mixture was sealed and stirred at 25°C. for eighteen hours. Evaporation of the solvent afforded the titleproduct as a white solid. ¹H-NMR(D₂O) 1.6-1.75 (m, 6H), 2.1 (s, 6H), 2.3(dd, 2H), 2.48 (t, 2H), 3.1 (t, 2H), 3.28 (t, 2H); Mass Spectra,M+H=184.

EXAMPLE 313 2-(Methylimino)pentamethylenimine Hydroiodide salt

To a solution of 0.2 g (0.00077 mol) of the thio-iminoether from exampleRKW-E in 3 mL of ethanol was added 2 mL of ethanol saturated withanhydrous methylamine. This mixture was sealed and stirred at 25° C. foreighteen hours. Evaporation of the solvent afforded the title product asa white solid. ¹H-NMR(D₂O) 1.6-1.7 (m, 4H), 2.45 (t, 2H), 2.7 (s, 3H),3.3 (t, 2H); Mass Spectra, M+H=113.

EXAMPLE 314 2-(Benzylimino)pentamethylenimine Hydroiodide salt

To a solution of 0.2 g (0.00077 mol) of the thio-iminoether from exampleRKW-E in 3 mL of ethanol was added 0.08 g (0.0008 mol) of benzylamine.This mixture was sealed and stirred at 25° C. for eighteen hours.Evaporation of the solvent afforded the title product as a white solid.Mass Spectra, M+H=189.

EXAMPLE 315 2-(Phenethylaminopropylimino)pentamethylenimine Hydroiodidesalt

To a solution of 0.2 g (0.00077 mol) of the thio-iminoether from exampleRKW-E in 3 mL of ethanol was added 0.09 g (0.0008 mol) ofphenethylamine. This mixture was sealed and stirred at 25° C. foreighteen hours. Evaporation of the solvent afforded the title product asa white solid.

¹H-NMR(D₂O) 1.6 (m, 4H), 2.4 (m, 2H), 2.8 (t, 2H), 3.1 (m, 2H), 3.4 (t,2H), 7.18-7.3 (m, 5H); Mass Spectra, M+H=203.

EXAMPLE 316 2-(p-Methoxyphenethylimino)pentamethylenimine Hydroiodidesalt

To a solution of 0.2 g (0.00077 mol) of the thio-iminoether from exampleRKW-E in 3 mL of ethanol was added 0.12 g (0.0008 mol) ofp-methoxyphenethylamine. This mixture was sealed and stirred at 25° C.for eighteen hours. Evaporation of the solvent afforded the titleproduct as a white solid. ¹H-NMR(D₂O) 1.6 (m, 4H), 2.18 (m, 2H), 2.75(t, 2H), 3.05 (m, 2H), 3.25 (t, 2H), 3.7 (s, 3H), 6.85 (d, 2H), 7.1 (d,2H); Mass Spectra, M+H=233.

EXAMPLE 317 2-(3-hydroxypropylimino)pentamethylenimine Hydroiodide salt

To a solution of 0.2 g (0.00077 mol) of the thio-iminoether from exampleRKW-E in 3 mL of ethanol was added 0.06 g (0.0008 mol) of3-hydroxypropylamine. This mixture was sealed and stirred at 25° C. foreighteen hours. Evaporation of the solvent afforded the title product asa white solid. ¹H-NMR(D₂O) 1.6-1.8 (m, 6H), 2.45 (t, 2H), 3.15 (t, 2H),3.28 (t, 2H), 3.55 (t, 2H)); Mass Spectra, M+H=157.

EXAMPLE 318 (5:3) 2-Imino-6-hexyl-pentamethylenimine Hydrochloride salt2-Imino-3-hexyl-pentamethylenimine Hydrochloride salt

To a solution of 10 g (0.06 mol) of 2-hexylcyclopentanone in 80 mL ofethanol and 60 mL of water was added 6.3 g (0.09 mol) of hydroxylaminehydrochloride and 9 g (0.11 mol) of sodium acetate. This mixture wasstirred for four hours at reflux, then for eighteen hours at 25° C. Thereaction mixture was concentrated to a reduced volume, diluted withethyl acetate, washed with three 200 mL portions of aqueous NaCl, dried(MgSO₄) filtered and concentrated to afford 10.2 g of the2-hexylcyclopentanoneoxime as a colorless oil. A solution of 8 g (0.044mol) of the oxime in 50 mL of acetone was treated with 48.4 mL (0.0484mol) of 1N NaOH at 0° C. To this stirred mixture was added 8.1 g (0.046mol) of benzenesulfonyl chloride dropwise. The resulting mixture wasstirred for eighteen hours at 25° C. The reaction mixture was pouredinto water and extracted with ethyl acetate. The organic layer wasseparated, washed with aqueous NaCl, dried (MgSO4), filtered andconcentrated to afford 8 g of a yellow oil. Chromatography (C-18, 10%acetonitrile/water to 70% acetonitrile/water) on 2 g of the yellow oilafforded 1.5 g of a 2:1 ratio of the 6-hexylvalerolactam to the3-hexylvalerolactam. To a solution of 1.5 g (0.01 mol) oftrimethyloxonium tetrafluoroborate in 35 mL of methylene chloride wasadded 1.5 g (0.0082 mol) of the above valerolactam mixture. This mixturewas stirred for 18 hours at 25° C. The reaction mixture was then dilutedwith ethyl acetate, washed with dilute potassium carbonate, dried(MgSO4), filtered through a patty of silica gel and concentrated toafford 0.6 g of the iminoether as a yellow oil. This oil was dissolvedin 40 mL of methanol and 0.18 g (0.0034 mol) of ammonium chloride wasadded. After stirring at reflux for 4 hours the mixture was stirred at25° C. for 18 hours. The reaction mixture was then concentrated toremove solvents. The residue was dissolved in water and extracted withethyl acetate. The aqueous layer was lyophilized to afford 0.16 g of a5:3 mixture of 2-Imino-6-hexyl-pentamethylenimine Hydrochloride salt to2-Imino-3-hexyl-pentamethylenimine Hydrochloride salt as a white solid.

¹H-NMR(D₂O) 0.72 (t, 3H), 1.1-1.9 (m, 14H), 2.3-2.62 (m, 2H), 3.2 (t,3-isomer), 3.38 (p, 6-isomer); Mass Spectra, M+H=183; Elemental analysisCalcd. for C₁₁H₂₃N₂Cl₁+3 N₁H₄Cl₁+3/4 H₂O: C, 33.64; H, 9.34; N,17.83.Found C,33.82; H, 9.20; N, 17.97.

EXAMPLE 319 (3:1) 2-Imino-6-heptyl-pentamethylenimine Hydrochloride salt2-Imino-3-heptyl-pentamethylenimine Hydrochloride salt

To a solution of 10 g (0.055 mol) of 2-heptylcyclopentanone in 75 mL ofethanol and 50 mL of water was added 5.8 g (0.083 mol) of hydroxylaminehydrochloride and 8.2 g (0.1 mol) of sodium acetate. This mixture wasstirred for four hours at reflux, then for eighteen hours at _(25°) C.The reaction mixture was concentrated to a reduced volume, diluted withethyl acetate, washed with three 200 mL portions of aqueous NaCl, dried(MgSO₄) filtered and concentrated to afford 10 g of the2-heptylcyclopentanoneoxime as a colorless oil. A solution of 8 g (0.04mol) the oxime in 50 mL of acetone was treated with 44 mL (0.044 mol) of1N NaOH at 0° C. To this stirred mixture was added 7.4 g (0.042 mol) ofbenzenesulfonyl chloride dropwise. The resulting mixture was stirred foreighteen hours at 25° C. The reaction mixture was poured into water andextracted with ethyl acetate. The organic layer was separated, washedwith aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford 8g of a yellow oil. Chromatography (C-18, 10% acetonitrile/water to 70%acetonitrile/water) on 2 g of the yellow oil, afforded 1.1 g of amixture of the 6-heptylvalerolactam to the 3-heptylvalerolactam. To asolution of 1 g (0.007 mol) of trimethyloxonium tetrafluoroborate in 25mL of methylene chloride was added 1.1 g (0.0056 mol) of the abovevalerolactam mixture. This mixture was stirred for 18 hours at 25° C.The reaction mixture was then diluted with ethyl acetate, washed withdilute potassium carbonate, dried (MgSO₄), filtered through a patty ofsilica gel and concentrated to afford 0.6 g of the iminoether as ayellow oil. This oil was dissolved in 40 mL of methanol and 0.17 g(0.0032 mol) of ammonium chloride was added. After stirring at refluxfor 4 hours the mixture was stirred at 25° C. for 18 hours. The reactionmixture was then concentrated to remove solvents. The residue wasdissolved in water and extracted with ethyl acetate. The aqueous layerwas lyophilized to afford 0.31 g of a 3:1 mixture of2-Imino-6-heptyl-pentamethylenimine Hydrochloride salt to2-Imino-3-heptyl-pentamethylenimine Hydrochloride salt as a white solid.¹H-NMR(D₂O) 0.7 (t, 3H), 1.05-1.9 (m, 16H), 2.3-2.6 (m, 2H), 3.2 (t,3-isomer), 3.35 (p, 6-isomer); Mass Spectra, M+H=197; Elemental analysisCalcd. for C₁₂H₂₅N₂Cl₁+0.6 N₁H₄Cl₁+1/3 H₂O: C, 53.22; H, 10.44; N,13.45.Found C,53.29; H, 10.53; N, 13.26.

EXAMPLE MVT-A 2-Imino-4-methyl-6-butyl-pentamethylenimineTrifluoroacetic acid salt

The title compound was prepared as in Example 319 from 3.4 g of2-butyl-4-methylcyclopentanone. A final purification by C-18 HPLC (0-40%acetonitrile/H2O, 30 min.) afforded 0.2 g of the title compound as anoily solid. 1H-NMR(D2O) 0.68-0.76 (m, 3H), 0.86 (d, J=6 Hz, 3H),1.12-1.24 (m, 4H), 1.28-1.76 (m, 4H), 1.92-2.16 (m, 2H), 2.46-2.58 (m,1H), 3.40-3.50 (m, 1H); Mass Spectra, M+H=169.

EXAMPLE MVT-B 2-Imino-4-methyl-6-allyl-pentamethylenimineTrifluoroacetic acid salt

The title compound was prepared as in EXAMPLE 319, from 5.3 g of2-allyl-4-methylcyclopentanone. A final purification by C-18 HPLC (0-40%acetonitrile/H2O, 30 min.) afforded 1.2 g of the title compound as anoily solid. 1H-NMR(D2O) 0.80-0.92 (m, 3H), 1.40-2.88 (m, 7H), 3.20-3.65(m, 1H), 4.96-5.16 (m, 2H), 5.60-5.78 (m, 1H); Mass Spectra, M+H=153.

EXAMPLE 320 Methyl 2-(1-propyl)cyclopentanone 2-carboxylate

Methyl cyclopentanone 2-carboxylate (Fluka) (14.2 g, 0.1 mol),1-iodopropane (Aldrich) (17 g, 0.1 mol), and potassium carbonate (10 g)were stirred in 100 ml of N,N-dimethylformamide (DMF) under nitrogen gasat 50° C. for 16 h. DMF was removed by rotary evaporation under reducedpressure. The residue was suspended in 500 ml of ethyl acetate and water(1/1 mixture). The ethyl acetate layer was separated and washed withwater, and then with sat. sodium chloride solution and dried over MgSO4.After rotary evaporation, the residue (crude product) weighed 14.6 g(78% yield). Mass Spectra: M+H=185. The crude product was used for thenext reaction without further purification.

EXAMPLE 321 2-(1-Propyl)cyclopentanone

Methyl 2-(1-propyl)cyclopentanone 2-carboxylate (10 g, 0.054 mol),sodium cyanide (2.9 g, 0.06 mol) and dimethylsulfoxide (100 ml) wasstirred at 1600° C. for 3 hr under nitrogen gas. After cooling, thereaction mixture was poured into ice-cooled water and extracted with 300ml of a mixture of ethyl ether/hexanes (1/1). The ethyl ether/hexaneslayer was separated, and was washed with saturated NaCl solution twice.After drying over MgSO4, the solvent was removed by rotary evaporation.The crude product was purified by silica gel column chromatography witha mixture of hexanes and ethyl acetate (7/3) as eluate. The productweighed 5.5 g (83%) yield). Mass Spectra: M+H=123.

EXAMPLE 322 2-Imino-6-(1-propyl)-pentamethylenimine trifluoroacetatesalt

2-Imino-6-(1-propyl)-pentamethylenimine was prepared as in example 322from 2-propylcyclopentanone. A final purification by revere-phased C18HPLC (0-50% acetonitrile/H2O, 30 min,) afforded 0.3 g of the titlecompound as a white semisolid. 1H-NMR (D2O) 0.70-0.78 (t, 3H), 1.15-1.88(m, 8H), 2.38-2.50 (m, 2H), 3.3-3.4 (m, 1H) Mass Spectra. M+H=255.

EXAMPLE 323 2-(1-butenyl)-2-carboethoxycyclohexanone

Sodium hydride, 60% in mineral oil (8,3 g, 200 mmol) was washed with 2portions of hexane and then dried under an N₂ flow. This was suspendedin dimethylformamide and ethyl 2-cyclohexanonecarboxylate (34.1 g, 200mmol) was added slowly under N₂ (note the foaming and exotherm), withcooling with a 25° C. water bath. After complete addition, the mixturewas stirred at 25° C. for ˜1 hour and the treagents added. The stirringmixture was heated to 50° C. for 18 hours (overnight). The reaction wasthen cooled to room temperature. The entire mixture was poured intowater, neutralized with dilute HCl and extracted with two portions of1:1 ether-hexane The combined organics were then washed with twoportions of water followed by saturated brine, then dried over MgSO₄,filtered and stripped giving 41.8 g of an impure mixture of products.Purification of the product by chromatography (silica gel,:5% methylt-butyl ether/90% hexane) gave 28.4 g of the title compound.

EXAMPLE 324 2-(1-butenyl)cyclohexanone

The reagents (1-butenyl)-2-carboethoxy cyclohexanone (11.2 g, 50 mmol),lithium chloride (10.6 g, 250 mmol), water (0.99 g, 55mmol), anddimethyl sulfoxide, (250 ml) were combined under N₂ and refluxed for 2hours. The reaction was then cooled to 25° C. The reaction mixture waspoured into water and extracted with two portions of 1:1 ether-hexane.The organic phases were combined and washed with two portions waterfollowed by saturated brine and then dried over MgSO₄. After filteringand stripping, the product was purified by fractional distillation at1.5 mm Hg. (The product boils at 65 to 70° C. at 1 to 2 mm Hg.), giving5.5 g of the desired title ketone.

EXAMPLE 325 2-(1-butenyl)cyclohexanone, oxime

2-(1-butenyl)cyclohexanone from example 324 (7.70 g, 51 mmol) wasconverted to the title compound by the method of Example 24 using 5.3 g(76 mmol) of hydroxylamine hydrochloride and 7.0 g (85 mmol) of NaOAc ina mixture of 70 mL of EtOH and 70 mL of water. The procedure produced8.48 g of the title material as a white solid.

EXAMPLE 326 hexahydro-7-(1-butenyl)-1H-azepin-2-one

The title compound of EXAMPLE 325 was converted to the present titlecompound by the method of EXAMPLE 29.

EXAMPLE 327 4,5,6,7-tetrahydro-2-methoxy-7-(1-butenyl)-3H-azepine

The product of Example 326 (1.34 g, 8 mmol) was reacted withtrimethyloxonium tetrafluoroborate (1.63 g, 11 mmol) by the method ofExample 26 to yield 1.5 g (100%) of the title material.

EXAMPLE 328 hexahydro-7-(1-butenyl)-1-H-azepin-2-imine,monohydrochloride

The product of Example 327 (1.5 g, 8 mmol) in 85 L of MEOH was reactedwith ammonium chloride (0.36 g, 6.8 mmol) by the method of Example 27 toyield 1.4 g (83%) of the title material.

Elemental analysis: C₁₀H₁₇N₂.HCl.0.45 H₂O (MW=210.83)

C H N Cl Calculated: 56.97 9.51 13.39 16.82 Found: 57.02 9.34 13.1616.86

¹H NMR (D₂O): δ5.75-5. 95 (m, 1H), 5. 1 (m, 2H), 3. 65 (tt, 1H) 2.75-2.5(m, 2H), 2.3 (m, 2H), 2.05-1.3 (m, 8H)

Biological Data

The activity of the above listed compounds as NO synthase inhibitors hasbeen determined in the following assays:

Citrulline Assay for Nitric Oxide Synthase

Nitric oxide synthase activity was measured by monitoring the conversionof [3H]-arginine to [3H]-citrulline. Mouse inducible nitric oxidesynthase (miNOS) was prepared from an extract of LPS-treated RAW 264.7cells and partially purified by DEAE-Sepharose chromatography. Rat brainconstitutive nitric oxide synthase (rnNOS) was prepared from an extractof rat cerebellum and partially purified by DEAE-Sepharosechromatography. Enzyme and inhibitors were incubated at 37° C. for 15minutes in a reaction volume of 100 mL with the following componentsadded to start the reaction: 50 mM Tris (pH 7.6), 1 mg/ml bovine serumalbumin, 1 mM DTT, 2 mM CaCl₂, 10 mM FAD, 10 mM tetrahydrobiopterin, 30mM L-arginine containing L-[2,3-3H]-arginine at 300 cpm/pmole and 1 mMNADPH. For constitutive NOS, 50 nM calmodulin was also added. Thereaction was terminated by addition of cold stop buffer containing 10 mMEGTA, 100 mM HEPES, pH 5.5 and 1 mM citrulline. [3H]-Citrulline wasseparated by chromatography on Dowex 50W X-8 cation exchange resin andradioactivity determined with a liquid scintillation counter.

Raw Cell Nitrite Assay

RAW 264.7 cells are plated to confluency on a 96-well tissue cultureplate grown overnight (17h) in the presence of LPS to induce NOS. A rowof 3-6 wells were left untreated and served as controls for subtractionof nonspecific background. The media was removed from each well and thecells are washed twice with Krebs-Ringers-Hepes (25 mM, pH 7.4) with 2mg/ml glucose. The cells are then placed on ice and incubated with 50 mLof buffer containing L-arginine (30 mM) +/− inhibitors for 1 h. Theassay is initiated by warming the plate to 37° C. in a water bath for 1h. Production of nitrite by intracellular iNOS is linear with time. Toterminate the cellular assay, the plate of cells is placed on ice andthe nitrite-containing buffer removed and analyzed for nitrite using apreviously published fluorescent determination for nitrite. T. P. Miskoet al, Analytical Biochemistry, 214, 11-16 (1993). All values are theaverage of triplicate wells and are compared to a background-subtractedinduced set of cells (100% value).

TABLE I cNOS Raw Cell Compound iNOS IC₅₀ [μM] IC₅₀ [μM] Example 1  2.113.3 60 Example 2  2.2 9.9 >1000 Example 3  43% * 10 μM  Example 4  4.62.4 14 Example 5  3.2 9.4 18 Example 6  0.055 0.285 Example 7  2.0 13.3Example 8  0.16 0.99 Example 9  1.496 2.01 Example 10 0.043 0.127Example 11 0.92 2.768 Example 12 5.1 32 1.8 Example 13 0.6 2.0 14Example 14 5.0 23 >1000 Example 15 8% @ 10 μM Example 16 0.8 4.0 4.3Example 17 0.8 2.7 28 Example 18 0.8 6.0 6.0 Example 19 42% @ 10 μM Example 20 1.0 5.0 160 Example 21 40 500 >1000 Example 22 30 1300 >1000Example 23 41% @ 10 μM  Example 60 1.1 32 3.5 Example 70 5.9 32 24Example 90 7.0 46 Example 96 9.3 1405  Example 107 3.8 342 15  Example108 0.14 19 0.57  Example 114 0.081 7.8 0.55  Example 173 42% @ 10 μM 49% @ 10 μM   Example 164 60% @ 100 μM 74% @ 100 μM  Example 170 3.4 53 Example 182 1.4 14  Example 188 0.55 106 0.65  Example 192 12 179 31 Example 198 2.1 652 3.3  Example 217 0.17 1.6 0.25

In Vivo Assay

Rats were treated with an intraperitoneal injection of 10 mg/kg ofendotoxin (LPS) with or without oral administration of the nitric oxicesynthase inhibitors. Plasma nitrites were measured 5 hourspost-treatment. The results show that the administration of the nitricoxide synthase inhibitor decreases the rise in plasma nitrites, areliable indicator of the production of nitric oxide, induced byendotoxin.

IP is the abbreviation for 2-iminopiperidine. LPS is the abbreviationfor endotoxin

TABLE II ED50's for Homoiminopiperidines determined in the Low Endotoxinin Rat Model Compound ED50 (mg/kg)  96 3.8 108 3.7 114 3.4 188 3.7 1985.0* (determined using iv infusion) All compounds administered p.o.unless otherwise noted

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A pharmaceutical composition comprising acompound having the formula:

and salts and pharmaceutically acceptable esters thereof, wherein: X isselected from the group consisting of methylene, SO, and SO₂ whereinmethylene may optionally be substituted with hydroxy, lower alkyl, loweralkoxy, amino, and haloalkyl groups; n is 1; R¹ is selected from thegroup consisting of lower alkenyl, lower alkynyl, lower alkoxy, lowerthioalkoxy, halogen, nitro, amino, cyano, haloalkyl, carboaryloxy,carboalkylaryloxy, alicyclic hydrocarbon, —SO₂NR⁵R⁶, —COR⁵, —SO₂R⁵,alkyl sulfoxide, aryl sulfoxide, alkyl sulfate, and aryl sulfate,wherein all said radicals can be optionally substituted with one or moreof the following: hydroxy, lower alkyl, lower alkenyl, lower alkynyl,lower alkoxy,lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano,carboalkoxy, carboaryloxy, carboxyalkylaryloxy, haloalkyl, —SO₂NR⁵R⁶ and—SO₂R⁵ wherein all said substitutions may be optionally substituted withone or more of the following: amino, carboxyl, carboalkoxy,carboaryloxy, carboxyalkylaryloxy and lower alkoxy; R² is selected fromthe group consisting of hydrogen, lower allyl, lower alkenyl, loweralkynyl, lower alkoxy, lower thioalkoxy, halogen, nitro, amino, cyano,haloalkyl, carboaryloxy, carboalkylaryloxy, alicyclic hydrocarbon,—CONR⁵R⁶, —SO₂NR⁵R⁶, —COR⁵, —SO₂R⁵, alkyl sulfoxide, aryl sulfoxidealkyl sulfate, and aryl sulfate, wherein all said radicals areoptionally substituted with one or more of the following: hydroxy, loweralkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower thioalkoxy,halogen, nitro, amino, carboxyl, cyano, carboalkoxy, carboaryloxy,carboxyalkylaryloxy, haloalkyl, —SO₂NR⁵R⁶ and —SO₂R⁵, wherein all saidsubstitutions are optionally substituted with one or more of thefollowing: amino, carboxyl, carboalkoxy, carboaryloxy,carboxyalkylaryloxy and lower alkoxy; R³, R⁴ are independently selectedfrom the group consisting of hydrogen, hydroxy, and alkyloxy; R⁵ and R⁶are independently selected from the group consisting of hydrogen, loweralkyl, and aryl; and together with at least one non-toxic pharmaceuticalacceptable carrier.
 2. The pharmaceutical composition as recited inclaim 1 wherein: X is methylene; R¹ is selected from the groupconsisting of lower alkenyl, lower alkynyl, haloalkyl and alicyclichydrocarbon wherein all said radicals are optionally substituted withone or more of the following: carboxyl, carboalkoxy, amino, loweralkoxy, lower thioalkoxy and lower alkyl wherein all said substitutionsmay be optionally substituted with one or more of the following: amino,carboxyl, and carboalkoxy; R² is selected from the group consisting ofhydrogen, lower alkyl, lower alkenyl, lower alkynyl, haloalkyl andalicyclic hydrocarbon wherein all said radicals can be optionallysubstituted with one or more of the following: carboxyl, carboalkoxy,amino, lower alkoxy, lower thioalkoxy and lower alkyl wherein all saidsubstitutions may be optionally substituted with one or more of thefollowing: amino, carboxyl, and carboalkoxy; R³, R⁴ are independentlyselected from the group consisting of hydrogen and hydroxy.
 3. Thepharmaceutical composition as recited in claim 1 wherein: X ismethylene; R¹ is selected from the group consisting of lower alkoxy,lower thioalkoxy, halogen, nitro, amino, cyano, and haloalkyl whereinall said radicals may optionally be substituted with hydroxy, loweralkyl, lower alkoxy, halogen, nitro, amino, carboxyl, cyano, andhaloalkyl groups; R² is selected from the group consisting of hydrogen,lower alkyl, lower alkoxy, lower thioalkoxy, halogen, nitro, amino,cyano, and haloalkyl wherein all said radicals may optionally besubstituted with hydroxy, lower alkyl, lower alkoxy, halogen, nitro,amino, carboxyl, cyano, and haloalkyl groups.
 4. The pharmaceuticalcomposition as recited in claim 1 wherein: X is methylene which mayoptionally be substituted with hydroxy, lower alkyl, lower alkoxy,amino, and haloalkyl groups; R¹ is selected from the group consisting oflower alkoxy of 1 to 6 carbon atoms, lower thioalkoxy of 1 to 6 carbonatoms, lower alkenyl of 2 to 6 carbon atoms, lower alkynyl of 2 to 6carbon atoms, halogen, nitro, amino, cyano, and haloalkyl and whereineach said radical may optionally be substituted with hydroxy, loweralkyl of 1 to 6 carbon atoms, lower alkoxy of 1 to 4 carbon atoms, loweralkenyl of 2 to 6 carbon atoms, lower alkynyl of 2 to 6 carbon atoms,halogen, nitro, amino, carboxyl, cyano, and haloalkyl groups; R² isselected from the group consisting of hydrogen lower alkyl of 1 to 6carbon atoms, lower alkoxy of 1 to 6 carbon atoms, lower thioalkoxy of 1to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, lower alkynylof 2 to 6 carbon atoms, halogen, nitro, amino, cyano, and haloalkyl andwherein each said radical may optionally be substituted with hydroxy,lower alkyl of 1 to 6 carbon atoms, lower alkoxy of 1 to 4 carbon atoms,lower alkenyl of 2 to 6 carbon atoms, lower alkynyl of 2 to 6 carbonatoms, halogen, nitro, amino, carboxyl, cyano, and haloalkyl groups. 5.The pharmaceutical compositions as recited in claim 1 wherein: X ismethylene; R¹ is selected from the group consisting of nitro, amino andcyano and wherein all said radicals may optionally be substituted withhydroxy, lower alkyl of 1 to 3 carbon atoms, lower alkoxy of 1 to 3carbon atoms, lower thioalkoxy of 1 to 3 carbon atoms, halogen, nitro,amino, carboxy and cyano; R² is selected from the group consisting ofhydrogen, lower alkyl of 1 to 3 carbon atoms, nitro, amino and cyano andwherein all said radicals may optionally be substituted with hydroxy,lower alkyl of 1 to 3 carbon atoms, lower alkoxy of 1 to 3 carbon atoms,lower thioalkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, carboxyand cyano.
 6. The pharmaceutical composition as recited in claim 1wherein: X is methylene; and R¹ is amino which may optionally besubstituted with hydroxy, lower alkyl of 1 to 3 carbon atoms, loweralkoxy of 1 to 3 carbon atoms, amino, lower thioalkoxy of 1 to 3 carbonatoms and carboxy; R² is selected from the group consisting of hydrogen,lower alkyl of 1 to 3 carbon atoms, and amino wherein all said radicalsmay optionally be substituted with hydroxy, lower alkyl of 1 to 3 carbonatoms, lower alkoxy of 1 to 3 carbon atoms, amino, lower thioalkoxy of 1to 3 carbon atoms and carboxy.
 7. A method of inhibiting nitric oxidesynthesis in a subject in need of such inhibition by administering atherapeutically effective amount of a compound having the formula:

and salts or pharmaceutically acceptable esters thereof, wherein: X isselected from the group consisting of methylene, nitrogen, oxygen, SO,and SO₂ wherein nitrogen and methylene may optionally be substitutedwith hydroxy, lower alkyl, lower alkoxy, amino, and haloalkyl groups; nis 1; R¹ and R², are independently selected from the group consisting ofhydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, loweralkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano,haloalkyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, alicyclichydrocarbon, heterocycly, aromatic hydrocarbon, —CONR⁵R⁶, —SO₂NR⁵R⁶,—COR⁵, —SO₂R⁵, alkyl sulfoxide, aryl sulfoxide, alkyl sulfate, and arylsulfate, wherein all said radicals can be optionally substituted withone or more of the following: hydroxy, lower alkyl, lower alkenyl, loweralkynyl, lower alkoxy,lower thioalkoxy, halogen, nitro, amino, carboxyl,cyano, carboalkoxy, carboaryloxy, carboxyalkylaryloxy, haloalkyl,—SO₂NR⁵R⁶ and —SO₂R⁵ wherein all said substitutions may be optionallysubstituted with one or more of the following: amino, carboxyl,carboalkoxy, carboaryloxy, carboxyalkylaryloxy and lower alkoxy; R³, R⁴are independently selected from the group consisting of hydrogen,hydroxy, and alkyloxy; R⁵ and R⁶ are independently selected from thegroup consisting of hydrogen, lower alkyl, and aryl.
 8. The method ofinhibiting nitric oxide synthesis as recited in claim 7 wherein; X isselected from the group consisting of methylene, nitrogen, and oxygen;R¹ and R², are independently selected from the group consisting ofhydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, haloalkyl,aromatic hydrocarbon and alicyclic hydrocarbon wherein all said radicalsare optionally substituted with one or more of the following: carboxyl,carboalkoxy, amino, lower alkoxy, lower thioalkoxy and lower alkylwherein all said substitutions may be optionally substituted with one ormore of the following: amino, carboxyl, and carboalkoxy; and R³, R⁴ areindependently selected from the group consisting of hydrogen andhydroxy.
 9. The method of inhibiting nitric oxide synthesis as recitedin claim 7 wherein; X is selected from the group consisting ofmethylene, nitrogen, and oxygen; R¹ and R² are independently selectedfrom the group consisting of hydrogen, hydroxy, lower alkyl, loweralkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano, andhaloalkyl wherein all said radicals may optionally be substituted withhydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino, carboxyl,cyano, and haloalkyl groups.
 10. The method of inhibiting nitric oxidesynthesis as recited in claim 7 wherein; X is methylene, nitrogen, oroxygen wherein nitrogen and methylene may optionally be substituted withhydroxy, lower alkyl, lower alkoxy, amino, and haloalkyl groups; R¹ andR² are independently selected from the group consisting of hydrogen,hydroxy, lower alkyl of 1 to 6 carbon atoms, lower alkoxy of 1 to 6carbon atoms, lower thioalkoxy of 1 to 6 carbon atoms, lower alkenyl of2 to 6 carbon atoms, lower alkynyl of 2 to 6 carbon atoms, halogen,nitro, amino, carboxyl, cyano, and haloalkyl and wherein each saidradical may optionally be substituted with hydroxy, lower alkyl of 1 to6 carbon atoms, lower alkoxy of 1 to 4 carbon atoms, lower alkenyl of 2to 6 carbon atoms, lower alkynyl of 2 to 6 carbon atoms, halogen, nitro,amino, carboxyl, cyano, and haloalkyl groups.
 11. The method ofinhibiting nitric oxide synthesis as recited in claim 7 wherein; X ismethylene, nitrogen, or oxygen; R¹ and R² are independently selectedfrom the group consisting of hydrogen, hydroxy, lower alkyl of 1 to 3carbon atoms, nitro, amino, carboxyl and cyano and wherein all saidradicals may optionally be substituted with hydroxy, lower alkyl of 1 to3 carbon atoms, lower alkoxy of 1 to 3 carbon atoms, lower thioalkoxy of1 to 3 carbon atoms, halogen, nitro, amino, carboxyl and cyano.
 12. Themethod of inhibiting nitric oxide synthesis as recited in claim 7wherein; X is methylene, nitrogen, or oxygen; and R¹ and R² areindependently selected from the group consisting of hydrogen, hydroxy,lower alkyl of 1 to 3 carbon atoms, amino, and carboxyl and wherein allsaid radicals may optionally be substituted with hydroxy, lower alkyl of1 to 3 carbon atoms, lower alkoxy of 1 to 3 carbon atoms, amino, lowerthioalkoxy of 1 to 3 carbon atoms and carboxyl.
 13. A method ofselectively inhibiting nitric oxide synthesis produced by inducible NOsynthase over NO produced by the constitutive forms of NO synthase in asubject in need of such inhibition by administering a therapeuticallyeffective amount of a compound having the formula:

and salts and pharmaceutically acceptable esters thereof, wherein: X isselected from the group consisting of methylene, nitrogen, oxygen, SO,and SO₂ wherein nitrogen and methylene may optionally be substitutedwith hydroxy, lower alkyl, lower alkoxy, amino, and haloalkyl groups; nis 1; R¹ and R², are independently selected from the group consisting ofhydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, loweralkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano,haloalkyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, alicyclichydrocarbon, heterocycly, aromatic hydrocarbon, —CONR⁵R⁶, —SO₂NR⁵R⁶,—COR⁵, —SO₂R⁵, alkyl sulfoxide, aryl sulfoxide, alkyl sulfate, and arylsulfate, wherein all said radicals can be optionally substituted withone or more of the following: hydroxy, lower alkyl, lower alkenyl, loweralkynyl, lower alkoxy,lower thioalkoxy, halogen, nitro, amino, carboxyl,cyano, carboalkoxy, carboaryloxy, carboxyalkylaryloxy, haloalkyl,—SO₂NR⁵R⁶ and —SO₂R⁵ wherein all said substitutions may be optionallysubstituted with one or more of the following: amino, carboxyl,carboalkoxy, carboaryloxy, carboxyalkylaryloxy and lower alkoxy; R³, R⁴are independently selected from the group consisting of hydrogen,hydroxy, and alkyloxy; R⁵ and R⁶ are independently selected from thegroup consisting of hydrogen, lower alkyl, and aryl.
 14. A method ofselectively inhibiting nitric oxide synthesis produced by inducible NOsynthase over nitric oxide produced by the constitutive forms of NOsynthase in a subject in need of such selective inhibition byadministering a therapeutically effective amount of a pharmaceuticalcomposition as recited in claims 1, 2, 3, 4, 5 or
 6. 15. A method oflowering nitric oxide levels in a subject in need of such byadministering a therapeutically effective amount of a compound havingthe formula:

and salts and pharmaceutically acceptable esters thereof, wherein: X isselected from the group consisting of methylene, nitrogen, oxygen, SO,and SO₂ wherein nitrogen and methylene may optionally be substitutedwith hydroxy, lower alkyl, lower alkoxy, amino, and haloalkyl groups; nis 1; R¹ and R², are independently selected from the group consisting ofhydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, loweralkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano,haloalkyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, alicyclichydrocarbon, heterocycly, aromatic hydrocarbon, —CONR⁵R⁶, —SO₂NR⁵R⁶,—COR⁵, —SO₂R⁵, alkyl sulfoxide, aryl sulfoxide, alkyl sulfate, and arylsulfate, wherein all said radicals can be optionally substituted withone or more of the following: hydroxy, lower alkyl, lower alkenyl, loweralkynyl, lower alkoxy,lower thioalkoxy, halogen, nitro, amino, carboxyl,cyano, carboalkoxy, carboaryloxy, carboxyalkylaryloxy, haloalkyl,—SO₂NR⁵R⁶ and —SO₂R⁵ wherein all said substitutions may be optionallysubstituted with one or more of the following: amino, carboxyl,carboalkoxy, carboaryloxy, carboxyalkylaryloxy and lower alkoxy; R³, R⁴are independently selected from the group consisting of hydrogen,hydroxy, and alkyloxy; R⁵ and R⁶ are independently selected from thegroup consisting of hydrogen, lower alkyl, and aryl.
 16. A method oflowering nitric oxide levels in a subject in need of such byadministering a therapeutically effective amount of a pharmaceuticalcomposition as recited in claims 1, 2, 3, 4, 5 or
 6. 17. Apharmaceutical composition comprising a compound having the formula:

and salts and pharmaceutically acceptable esters thereof, wherein: X ismethylene which may optionally be substituted with hydroxy, lower alkyl,lower alkoxy, amino, and haloalkyl groups; n is 0; R¹ is selected fromthe group consisting of lower alkoxy, halogen, nitro, amino, cyano, andhaloalkyl wherein all said radicals may optionally be substituted withhydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino, carboxyl,cyano, and haloalkyl groups R² is selected from the group consisting ofhydrogen, lower alkyl, lower alkoxy, halogen, nitro, amino, cyano, andhaloalkyl wherein all said radicals may optionally be substituted withhydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino, carboxyl,cyano, and haloalkyl groups.
 18. The pharmaceutical composition definedin claim 17 wherein: X is methylene which may optionally be substitutedwith hydroxy, lower alkyl, lower alkoxy, amino, and haloalkyl groups; R¹is selected from the group consisting of lower alkoxy of 1 to 6 carbonatoms, halogen, nitro, amino, cyano, and haloalkyl and wherein each saidradical may optionally be substituted with hydroxy, lower alkyl of 1 to6 carbon atoms, lower alkoxy of 1 to 4 carbon atoms, lower alkenyl of 2to 6 carbon atoms, lower alkynyl of 2 to 6 carbon atoms, halogen, nitro,amino, carboxyl, cyano, and haloalkyl groups; R² is selected from thegroup consisting of hydrogen, lower alkyl of 1 to 6 carbon atoms, loweralkoxy of 1 to 6 carbon atoms, halogen, nitro, amino, cyano, andhaloalkyl and wherein each said radical may optionally be substitutedwith hydroxy, lower alkyl of 1 to 6 carbon atoms, lower alkoxy of 1 to 4carbon atoms, lower alkenyl of 2 to 6 carbon atoms, lower alkynyl of 2to 6 carbon atoms, halogen, nitro, amino, carboxyl, cyano, and haloalkylgroups.
 19. The pharmaceutical compositions defined in claim 17 wherein:X is methylene which may optionally be substituted with lower alkyl,lower alkoxy and amino; R¹ is selected from the group consisting ofnitro, amino, and cyano and wherein all said radicals may optionally besubstituted with hydroxy, lower alkyl of 1 to 3 carbon atoms, loweralkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, carboxyl or cyano;R² is selected from the group consisting of hydrogen, lower alkyl of 1to 3 carbon atoms, nitro, amino, and cyano and wherein all said radicalsmay optionally be substituted with hydroxy, lower alkyl of 1 to 3 carbonatoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino,carboxyl or cyano.